VHA Meeting Pham How To Do Research

United States Experiences in Data Registries: The Acute Coronary Syndrome Patients 1.72 Million Hospital Discharges for ACS STEMI 0.42 Million Discharges per Year UA/NSTEMI 1.3 Million D

What They Have in Common?

“Vision: Build & They Will Come”

How to Conduct A Successful Clinical

Research?

Dr Phạm Thành An

Why Clinical Research in Viet Nam?

 Nearly 3.7 billion people are living in Asia or 56.3% of worldwide population

 ~88 million in Viet Nam

 JUPITER trial, 2008: N=17,802 patients; 71.4%

White; 12.4% Black; 12.6% Hispanic; 3.6%

Other/Unknown ethic group

 ALLHAT trial, 2002: N=42,418; 47.2% White; 31.9% Black; 15.8% Hispanic; 5.1% Other

 More participation to balance study subjects and

principal investigators is needed

 Rosuvastatin, 2004 - FDA approved starting dose is 5mg for Asians & 10mg for Caucasians based on kinetic data in Asia

 Isoniazid (INH), 1976 - majority of Asians were

discovered to be fast acetylators

(1) Crestor, Prescribing Information, 2009; (2) Myers FH, Rev of Med Pharm, 5 th Ed, Lange Med Publications; (3) Ridker PM, JUPITER Study,

NEJM, 2008, 359:2195-207; (4) ALLHAT Study Group, JAMA, 2002: 288:2981-97; (5) US Census Bureau, World Population Estimates

Work-in-Progress - 2010

Article-in-Press

SHARP Trial

Top Enrolling Countries

France 1.7% Argentina 1.5%

Role & Responsibility

personally conducted and supervised according to

 Signed investigator statement,

 Investigational plan,

 Applicable regulations

after study discontinuation

What Are the Basic Elements for Successful Clinical Research? 4 R’s

 New Knowledge/Discovery

 Evidence-Based Question

 Robust Registry Database

 Comprehensive/Accurate Reporting System

 Large Pool of Eligible Patients

 Good Follow Up Mechanism

 Research Staff

 Large Network/Consortium

Successful Data Registry Requirement

 Disease Prevalence

 Generate research hypothesis

United States Experiences in Data Registries:

The Acute Coronary Syndrome Patients

1.72 Million Hospital Discharges for ACS

STEMI 0.42 Million Discharges per Year

UA/NSTEMI 1.3 Million Discharges per Year

ACS is an umbrella term covering any group of clinical symptoms

compatible with acute restriction of blood flow to the heart muscle

Acute Coronary Syndrome (ACS), UA/NSTEMI (Unstable

Angina/Non ST-Segment Elevation Myocardial Infarction) & STEMI (ST-Segment Elevation Myocardial Infarction):

Why Targeted ACS?

 Implement cycle of continuous quality improvement (CQI) to

promote guideline recommendations

 Reduce in-hospital mortality for NSTE ACS patients via early risk stratification and implementation of evidence-based care

 Educational/Research/Publishing Opportunities

Technology Used in CRUSADE

CRUSADE Report

Overall Adherence Trends Over Time

The Train Speeds Up….

Faster Cardiac Catheterization*

CRUSADE Report

CRUSADE Report

Need Right Drug but Also Right Dose Excessive

Antithrombotic Dosing by Age

12.5

28.7

8.5 12.5

(3)

MT (0)

WY (0)

CO (8)

NM (2)

ND (1)

SD (2)

NE (4)

KS (3)

OK (8)

TX (17)

MN (4)

IA (4)

MO (12)

AR (4)

LA (8)

WI (5) MI

(24) MI

UT (1)

AZ (9)

HI (1)

IL (15)

IN (9) KY (8) TN (15)

MS (7)

AL (11)

GA (15)

FL (33)

SC (6)

NC (13)

VA (16)

OH (30) WV (3)

PA (39)

NY (36)

MD (13)

ME (1)

Summary – Data Registry

 Vietnamese experience; Made-in-Vietnam; Vietnamese Progress

 Industry, professional societies, World Health Organization (WHO)

 Educational/Research/Publishing Opportunities

 Determine current state of awareness of and adherence to the ACC/AHA Non-ST-segment Elevation (NSTE) ACS Guidelines

 Implement cycle of continuous quality improvement (CQI) to

promote guideline recommendations

 Reduce in-hospital mortality for NSTE ACS patients via early risk stratification and implementation of evidence-based care

Patients Randomized by Country

187

330 292

Background – SEAS Trial

 Evidence suggests calcific aortic stenosis is the product of active inflammatory process

 Histopathologic studies have demonstrated that development and progression of calcific AS are based on an active process that shares a number of similarities with atherosclerosis

 Several studies also have suggested that AS and atherosclerosis have a number

of risk factors in common, such as hypercholesterolemia, elevated lipoprotein(a), smoking, hypertension, and diabetes

Why statins?

 Aortic valve lesions simulate atheroma

 HMG-CoA reductase inhibitors have been shown to slow the progression of coronary atherosclerotic

Before Study Hypothesis

slower progression of aortic stenosis

 Aortic peak velocity

 Aortic mean gradient

 Aortic valve area

Bellamy et al J Am Coll Cardiol 2002;40:1723

Study N Patient Characteristics Study Groups Parameter

AV calcium on electron beam tomography

Lower LDL-C associated with slower progression of AV

>125 mg/dl with statin

vs LDL-C <125 mg/dl without statin

Peak transvalvular gradient on echocardiogram

Lower LDL-C and statin use associated with slower progression of AS

AV area and peak gradient on echocardiogram

Statin use associated with slower progression of AS

AV calcium on electron beam tomography

Statin use associated with slower progression of AV

Statin therapy vs no statin therapy

AV area and mean gradient

Aortic-jet velocity and peak transvalvular gradient on echocardiogram

Statins, but not ACE inhibitors, were associated with slower AS progression, independent of

LDL-C levels

Retrospective Studies - Aortic Stenosis

Study N

Patient Characteristi

cs

Study Groups

on echocardiogra

m; AV calcification

by CT

No difference between groups

m

Rosuvastatin associated with slower progression

of AS

AS Prospective Completed Studies

 4 Weeks placebo/diet run-in

 Simvastatin 40 mg + ezetimibe 10 mg or placebo

 Median duration: 4.5 year (minimum follow-up 4 years)

Secondary Endpoints

Aortic Valve Events

 Aortic Valve Replacement

Other Objectives

Echocardiography

Safety

 Doppler jet velocity ≥2.5 - ≤4.0 m/sec

Exclusion Criteria

 Statin therapy or indication for statins

 Coronary heart disease

 Other important valvular disease

 Significant mitral valve stenosis or regurgitation

 Severe or predominant aortic regurgitation

 Rheumatic valvular disease or AV prosthesis or subvalvular (hypertrophic, obstructive

cardiomyopathy) or supravalvular AS

 Diabetes Mellitus

 Other conditions precluding participation

Baseline Lipids and Lipoproteins

Fasting Serum Lipid and Lipoprotein Levels at Baseline (n=1,873)

Concentration (mmol/L)

Concentration (mg/dl)

Primary Endpoint MACE

Intention to Treat Population

Years in Study

0 10 20 30 40 50

2nd EP: Aortic Valve Events

Aortic Valve Replacement

Peak Aortic - Jet Velocity

Intention to Treat Population

EZ/Simva 10/40 mg

2nd EP: Ischemic CV Events

Coronary Artery Bypass Grafting (CABG)

0 10 20

All Cause Mortality

Intention to Treat Population

Clinical Adverse Events (AE)- Safety

Placebo EZ/ Simva

Any serious AE (SAE) 463 468

Drug d/c due to SAE 79 77

Musculoskeletal AE 181 165 0.28

All Patients as Treated Population

Marketing Your Study Site

Network

 www.clinicalinvestigators.com ; www.acurian.com

Research Organization (CROs)

Site Profile for Marketing Distribution

population

performance

Resources & Networking

 Clinical Trial Networks Best Practices

 www.ctnbestpractices.org

 International/Academic Collaboration

 Duke Clinical Research Institute (DCRI)

 www.dcri.duke.edu

 TIMI Study Group – www.TIMI.org

 Oxford University – www.ctsu.ox.ac.uk/projects

 Clinical Trial Registries – www.clinicaltrials.gov

 Clinical Trial Results – www.clinicaltrialresults.org

 Better treatment strategies

 New/better treatment options

 Reduce morbidity/mortality

Questions & Comments