1. Obligatory Drug-Device Interactions-Why The Critical Path
Obligatory Drug-Device Interactions-Why The Critical Path? An Academic View
Mitchell W. Krucoff, MD, FACC
Professor, Medicine/Cardiology
Duke University Medical Center
Director, Cardiovascular Devices Unit
Duke Clinical Research Institute

2. Mitchell W. Krucoff, MD DISCLOSURES Consulting Fees
Biosensors International, Terumo Medical Corporation
Grants/Contracted Research
Boston Scientific Corporation, Medtronic CardioVascular, Inc.
Honoraria
Abbott Vascular, Cordis, a Johnson & Johnson company

3. Critical Path Initiatives: March 2004

4. 2006 FDA – Duke/DCRI Memorandum Of Understanding (MOU)
Establish Public/Private Partnership (PPP)
Leverage resources / expertise
Advance pre-competitive assessment tools
Advance public health
Cardiac Safety Research Consortium (CSRC)

6. Discontinuation of Anti-platelet Therapy and Risk for ST
Overall stent thrombosis = 1.3% (P=0.09, N=2229)
Incidence (%)
Premature discontinuation of antiplatelet therapy was a major significant univariate predictor of stent thrombosis.
The cumulative incidence of thrombosis was 29% (5 of 17 patients), with a hazard ratio of 152 (95% Confidence interval; 52 to 442; P<0.001); clopidogrel was discontinued in one patient.
Other significant univariate predictors included prior brachytherapy, renal failure, bifurcation with 2 stents, bifurcation lesions, and diabetes, with respective cumulative thrombosis rates of 8.7%, 6.2%, 3.9%, 3.6%, and 2.5% (P<0.05).
Unstable angina, thrombus, and unprotected left main were not significant univariate predictors of thrombosis.
Unstable angina
Thrombus
Diabetes
Unprotected left main
Bifurcation
Renal failure
Prior brachy Rx
Premature antiplateletdiscont’d
Iakovou et al. JAMA. 2005;293:2126.
Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:

7. The Public Health Question
10,000,000 DES patients
Permanent implants
Linear hazard %: 50,000 death/MI per annum
Growing every year

8. DES Thrombosis: A Novel Regulatory Domain: Obligatory Drug-Device Safety Interaction
Combination drug-on-device (Medical Device Reg)
Studied in de-novo 1-vessel PCI to reduce restenosis
Clopidogrel/Prasugrel:
Thienopyridines (Drug Reg)
Studied in ACS patients
Public health issue:
Crossover of drug-device “cultures”
No clear regulatory predicate
Combinations of new DES and new DAP
Post-market “real world” population

9. DES & Extended Dual Antiplatelet Therapy: What It Takes: Collaboration
Regulatory
FDA:
CDER
CDRH
Off Comm
E.U.
Austria
U.K.
Sweden
Japan:
MHLW
PMDA
Societies
ACC
SCAI
ESC
Academia
Duke
Harvard
Cleveland Clinic
Columbia
U of NM
Wash Hrt Ctr
London School of Hyg & Trop Med
CVPath
Industry
Abbott
Medtronic
BSCI
Cordis/J&J
Biosensors
OrbusNeich
Eli Lilly (Daichi)
Sanofi
BMS
Federal
NIH
AHRQ

10. Dual Antiplatelet Therapy (DAPT) RCT
Initial
Procedure –
Enrollment
Randomization
(All Eligible Subjects)
End of
Treatment
End of
Follow Up
m m m
30 m DAPT arm
Obs
Double Blind Placebo Controlled RCT
12 vs 30m randomization in subjects clear and on treatment at 12m
Stratified by lesion and clinical complexity
Co primary endpoints: ST and MACCE,
Safety endpoint: Major bleed
33 months follow up, to include 3 month “rebound period”
Simultaneous RCT of 12 vs 30m DAPT in BMS
Both clopidogrel and prasugrel R
DES n = 12,196
BMS n = 4,320
DES n = 15,245
BMS n = 5,400
Open label DAPT
Source patients denovo + PMS studies
12 m DAPT arm
Obs

11. SAFARI
April 2009

12. Trans-Radial Education, Assessment &Training The TREAT Registry
Obligatory Device-Drug Interaction:
Impact of device technique on drug safety (bleeding) profiles

13. Obligatory Drug-Device Safety Interactions: Critical Path Initiatives
Collaborative, transparent PPP forum:
Unique resource for combined expertise, including CDER, CDRH, OC
Opportunity to focus on pre-competitive regulatory & public health issues
Provides a “thinktank/incubator” environment to launch tangible programs
Individual programs require tailored management and operations solutions

14. Obligatory Drug-Device Interactions-Why The Critical Path
Obligatory Drug-Device Interactions-Why The Critical Path? An Academic View
Mitchell W. Krucoff, MD, FACC
Professor, Medicine/Cardiology
Duke University Medical Center
Director, Cardiovascular Devices Unit
Duke Clinical Research Institute