Paper :: Prevention

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

PAPER :: Prevention The Detection of Ischemia in

Asymptomatic Diabetics (DIAD study) JAMA. 2009;301(15):1547-1555

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 But the utility of screening patients with type

2 DM for asymptomatic CAD is controversial.

ABOUT MPI – MYOCARDIAL PERFUSION IMAGING

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.

Method

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

Inclusion criteria (3)

Exclusion criteria (7)

Method

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

Exclusion criteria (7)

เหลือ1,700 เขา้รว่ม 1,123 (66%) 14 centers in USA and Canada

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

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

METHOD - Cardiac event

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

Primary end point Secondary end points

METHOD – Statistic analysis

Data Statistic analysis

SAS statistical software version 9.1Bivariate associations, according to loss F/U, randomization status, and factors associated with cardiac events

t testsWilcoxon Rank sum, 2, and Fisher

Changes in medications McNemar test and logistic regression.

Hazard ratios (HRs) comparing(1)Events in screened vs

nonscreened(2)Events in participants with

normal MPI vs nonperfusion, small or moderate or large perfusion defects

Cox proportional hazards regression

Was the assignment of patients to screening randomised ?1A – YesNoUnclear

Were measures objective or were the patients and clinicians kept “blind” to which treatment was being received?

3 – YesNoUnclear

RESULT Mean (SD) 4.8 (0.9) years Median 5 years F/U was complete 97% at 3.5

years Last data collected in Sep 2007

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

Were the groups similar at the start of the trial?1B – YesNoUnclear

Aside from the allocated screened, were groups screened equally?

2A – YesNoUnclear

Were all patients who entered the trial accounted for? – and were they analysed in the groups to which they were randomised?

2B – YesNoUnclear

RESULT :: Primary outcomes

RESULT :: Primary outcomes

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

RESULT :: Primary outcomes

RESULT :: Primary outcomes

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.

Cardiac event +ve

Cardiac event - ve

Test + ve 7 106

Test - ve 8 401

RESULT :: Secondary outcomes

RESULT :: Secondary outcomesCoronary angiography and revascularization

Repeat stress MPI 3 year (n = 358) : improved

RESULT :: Secondary outcomesMedical treatment

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

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

How large was the screening effect?Re1– YesNoUnclear

Hazard Ratio =0.88Relative Risk = 2.7%/3.0% = 0.9Absolute 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

How precise was the estimate of the treatment effect?Re2– YesNoUnclear

COMMENT Cardiac event rates ในประชากรที่ศึกษา 0.6% per

year อัตราน้อยกวา่ท่ีคาดการณ์ไว้ เหน็ผลการเกิด cardiac event

จากการคัดกรองได้ไมช่ดัเจน อัตราต่ำ่ากวา่บางการศึกษาอ่ืนท่ีมมีาก่อน (retrospective

analysis; cardiology laboratories) 3-4 เท่า เนื่องจาก ประชากรในการศึกษาอ่ืนนัน้ๆ มี risk มากกวา่

อัตราใกล้เคียงกับ 3 การศึกษาในการ screening asymptomatic ischemia in type 2 DM

ACCORD study = 1.4% per year มกีารก่ำาหนด primary outcome definition, selection older patient with specific additional risk

COMMENT ความผิดปกติท่ีตรวจพบจากการท่ำา MPI สมัพนัธกั์บ

อุบติัการณ์การเกิด cardiac event แมว้า่จะมี PPV ต่ำ่า และยงัมโีอกาสเกิด cardiac event ได้แมใ้นคนท่ี ผล MPI ปกติ

Cardiac outcomes ท่ีดี เกิดจาก Aggressive guideline-driven management

of cardiac risk factor การ screen ซ่ำ้าท่ี 3 ปี พบวา่มี resolution of

inducible ischemia

COMMENT ผู้ป่วยท่ีคาดวา่จะมี intermediate cardiac risk

Long-standingdiabetes Older age Obesity

ผู้ป่วยท่ีคาดวา่จะมี high cardiac risk Poor ability to exercise

จากผล PPV, NPV พบวา่มากกวา่ครึง่หน่ึงของcardiac event เกิดใน normal screening test

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

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 does not appear to affect

overall outcome. Routine screening of millions of asymptomatic

diabetic patients would be prohibitively expensive

(External Validity/Applicability)

Will the results help me in caring for my patient?

Screening criteriaCriteria This study

The burden of sufferingDeath, Disease, Disability, Discomfort, Dissatisfaction, Destitution

The quality of screening testSensitivity and specificity, Simplicity, Safety, CostEffectiveness of TreatmentCost-effectivenessLongevity