Paper :: Prevention

1. Cardiac Outcomes After Screening for Asymptomatic Coronary Artery Disease in Patients With Type 2 DiabetesThe DIAD Study: A Randomized Controlled Trial

2. Paper :: Prevention • The Detection of Ischemia in Asymptomatic Diabetics (DIAD study) • JAMA. 2009;301(15):1547-1555

3. Context • Coronary artery disease (CAD) : major cause of mortality and morbidity in patients with type 2 DM • Often asymptomatic until MI or sudden cardiac death • Type 2 DM = CAD risk equivalent • Current standard of care emphasizes the reduction of cardiovascular risk factors • Butthe utility of screening patients with type 2 DM for asymptomatic CAD is controversial.

4. About MPI – Myocardial Perfusion Imaging

5. Objective • To assess whether routine screening for CAD identifies patients with type 2 DM as being at high cardiac risk and whether it affects their cardiac outcomes.

6. Method Inclusion criteria (3) Exclusion criteria (7) • Age 50-75 years • Onset of type 2 DM occurred at age  30 years • No history of ketoacidosis • Angina pectoris or chest discomfort • Stress test or CAG within the prior 3 years • History of MI, heart failure, or coronary revascularization • Abnormal rest EKG results • Pathological Q waves • Ischemic (1 mm depression) ST segments • Deep negative T waves, or • Complete LBBB

7. Method Exclusion criteria (7) • Any clinical indication for stress testing • Active bronchospasm precluding the use of adenosine • Limited life expectancy due to cancer or end-stage renal or liver disease

8. เหลือ1,700 เข้าร่วม1,123 (66%) 14 centers in USA and Canada

9. Method • Between July 2000 and August 2002. (25 month) • DIAD protocol • The study design and procedures were explained by a member of the local research team • All participants • History : health status, medications, intervening cardiac events, additional stress testing, CAG, and revascularizationat 6-month intervals • Physical examination : diabetic neuropathy, cardiac autonomic dysfunction • Lab : Blood and urine laboratory testing

10. Method • Randomization • Sequential identification number at each site • A corresponding sealed envelope was opened • Random permuted blocks (block size 6) sequence 1:1 • 561 participants was screening with adenosine Tc-99m sestamibi MPI, interpreted by nuclear cardiologists

12. Method - Cardiac event Primary end point Secondary end points • Nonfatal MI • Cardiac death-included fatal MI (within 30 days) • Death due to heart failure or arrhythmia • Sudden cardiac death • Unstable angina • Heart failure • Stroke • Coronary revascularization

13. Method – Statistic analysis

14. Was the assignment of patients to screening randomised ? 1A – Yes No Unclear

15. Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received? 3 – Yes No Unclear

16. Result • Mean (SD) 4.8 (0.9) years • Median 5 years • F/U was complete 97% at 3.5 years • Last data collected in Sep2007

17. ResultBaseline characteristic overview • Age • DM duration (year) • BMI • HbA1C • Serum creatinine • Clinical risk factor • Gender • Race • DM treatment • DM complication • Current smoking • Family history of premature CAD

20. Were the groups similar at the start of the trial? 1B – Yes No Unclear

21. Aside from the allocated screened, were groups screened equally? 2A – Yes No Unclear

22. Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised? 2B – Yes No Unclear

23. Result :: Primary outcomes

24. Result :: Primary outcomes

25. Result :: Primary outcomes • 32 cardiac event (17 MI + 15 cardiac death) • Overall cumulative 5-year cardiac event rate = 2.9 % (average 0.6% per year) Hazard ratio = 0.88; 95% CI 0.44-1.8; log-rank 0.12; P = 0.73

26. Result :: Primary outcomes

27. Result :: Primary outcomes

28. Result :: Primary outcomes • Mean (SD) MPI defect size[P = 0.12] • Cardiac event 4.1% (6.6%) • No cardiac event 1.4% (2.2%) • Negative predictive value of having a normal MPI = 98% (401of 409). • Positive predictive value • 6% (7 of 113) of patients for any MPI abnormality • 12% (4 of 33) of patients for moderate or large MPI defects.

30. Result :: Secondary outcomes

31. Result :: Secondary outcomesCoronary angiography and revascularization Repeat stress MPI 3 year (n = 358) : improved

32. Result:: Secondary outcomesMedical treatment

33. Result:: Secondary outcomesPredictors of cardiac events • Male sex • Diabetes duration • Microalbuminuria/proteinuria • Serum creatinine • Symptomsof peripheral neuropathy • Diminished peripheral sensation • Cardiac autonomic dysfunction • Peripheral vascular disease • Elevated LDL • Family history of premature CAD

34. Independent role of • Male sex • Serum creatinine • Cardiac autonomic dysfunction • Peripheral vascular disease • LDL level

35. How large was the screening effect? Re1– Hazard Ratio =0.88 Relative Risk = 2.7%/3.0% = 0.9 Absolute Risk Reduction = 3.0%-2.7% = 0.3% Relative Risk Reduction = 1.0-0.9 = 0.1 or 10% Number Needed to Screen = 1/0.003 = 333 Yes No Unclear

36. How precise was the estimate of the treatment effect? Re2– Yes No Unclear

37. Comment • Cardiac event ratesในประชากรที่ศึกษา 0.6% per year • อัตราน้อยกว่าที่คาดการณ์ไว้ เห็นผลการเกิด cardiac event จากการคัดกรองได้ไม่ชัดเจน • อัตราต่ำกว่าบางการศึกษาอื่นที่มีมาก่อน (retrospective analysis; cardiology laboratories) 3-4 เท่า เนื่องจากประชากรในการศึกษาอื่นนั้นๆ มี risk มากกว่า • อัตราใกล้เคียงกับ 3 การศึกษาในการ screening asymptomatic ischemia in type 2 DM • ACCORD study = 1.4% per year มีการกำหนด primary outcome definition, selection older patient with specific additional risk

38. Comment • ความผิดปกติที่ตรวจพบจากการทำ MPI สัมพันธ์กับอุบัติการณ์การเกิด cardiac event แม้ว่าจะมี PPV ต่ำ และยังมีโอกาสเกิด cardiac event ได้แม้ในคนที่ผล MPI ปกติ • Cardiac outcomes ที่ดี เกิดจาก • Aggressive guideline-driven management of cardiac risk factor • การ screen ซ้ำที่ 3 ปีพบว่ามี resolution of inducible ischemia

39. Comment • ผู้ป่วยที่คาดว่าจะมี intermediate cardiac risk • Long-standingdiabetes • Older age • Obesity • ผู้ป่วยที่คาดว่าจะมี high cardiac risk • Poor ability to exercise • จากผล PPV, NPV พบว่ามากกว่าครึ่งหนึ่งของ cardiac event เกิดใน normal screening test

40. Limitations • Cardiac event rates were significantly lower than originally anticipated at the time of the design of the study • Not have the power to exclude a small difference between the screened and unscreened participants • Non protocol stress tests were done during F/U when clinically indicated in both groups • Screening led to only a modest reduction in subsequent diagnostic testing • In no-screening group : crossover to a physician-direct screening strategy and theoretically

41. Clinical implications • Routine screening for inducible ischemia in asymptomatic patients with type 2 DM cannot be advocated • Yield of detecting significant inducible ischemia is relatively low. • Overall cardiac event rate is low. • Routine screening doesnot appear to affect overall outcome. • Routine screening of millions of asymptomatic diabetic patients would be prohibitively expensive

42. Will the results help me in caring for my patient? (External Validity/Applicability)

43. Screening criteria