AHA 2012 LBT Commentary Trial to Assess Chelation Therapy (TACT) - - PowerPoint PPT Presentation

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AHA 2012 LBT Commentary Trial to Assess Chelation Therapy (TACT) Paul W Armstrong MD Sunday November 4 , 2012 Los Angeles Disclosure Statement Paul W. Armstrong MD Details available @ http://www.vigour.ualberta.ca Research Grants

SLIDE 1

Trial to Assess Chelation Therapy (TACT)

Paul W Armstrong MD Sunday November 4 , 2012 Los Angeles

AHA 2012 LBT Commentary

SLIDE 2

Disclosure Statement Paul W. Armstrong MD

Details available @ http://www.vigour.ualberta.ca

 Research Grants

 Boehringer Ingelheim  sanofi aventis  Merck  Astra Zeneca  Eli Lilly  GlaxoSmithKline  Regado Biosciences

 Consultant

 Regado Biosciences

 Data & Safety Monitoring Boards

 Roche  Orexigen  Lilly

2012

SLIDE 3

Balancing TACT in Context

CT is valuable effective & safe CT is likely unsafe, certainly ineffective & should be abandoned

Pro Con

Birmingham Technology Assessment Group Report 2002 Chappell & Jansen Ernst

SLIDE 4

Lamas Br. J. Cardiol. 2006, Heart.org 2009,AHJ 2012

 ~ 66,000 US pts Rx chelation in 2002 : ( to 111,000 in 2007)  ~ $5000 for full course of 40-50 infusions  Imposes significant patient burden & potential serious side effects  Challenging 7 yr operations: 2003-11:orginal plan 36 mo enrollment  Interim TACT progress 2006: 900 patients enrolled & > 25,000

infusions administered in ~ 100 US sites

 Trial stopped ~1500 pts Sept 2008: OHRP & FDA investigate ICF

process & trial conduct : corrective steps, then re-started June 2009

 Oct 2010 n=1708 vs planned 2372 pts: 85% power to detect 25%

RR in primary composite death, MI, stroke,coronary revasc & hospitalization angina

SLIDE 5

E v e n t R a t e

0 .0 0 .1 0 .2 0 .3 0 .4 0 .5

M o n th s s in c e ra n d o m iz a tio n

6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0

H a z a rd R a tio 9 5 % C I P -v a lu e E D T A :P la c e b o 0 .8 2 0 .6 9 ,0 .9 9 0 .0 3 5

P la c e b o E D T A C h e la tio n

N u m b er a t R isk E D T A C h ela tio n

8 3 9 7 6 0 7 0 3 6 5 0 5 8 8 5 3 7 5 1 1 4 7 6 4 2 7 3 5 8 2 2 9

P la ceb o

8 6 9 7 7 6 7 0 1 6 3 8 5 6 6 5 1 5 4 7 5 4 2 9 3 8 4 3 2 2 2 0 5

Death, MI, stroke, coronary revascularization, hospitalization for angina

TACT: Primary Endpoint Results

483 events : intergp diff=39

SLIDE 6

TACT : Primary Endpoint Components

1 2

HR (95%CI) 0.72(0.35-1.47)

Primary Endpoint

Death Myocardial infarction Stroke Coronary revasc. Hospitalization for angina

0.77(0.54-1.11) 0.81(0.64-1.02) 0.82(0.69-0.99) 0.93(0.70-1.25) 0.77(0.34-1.76) EDTA Better Placebo Better 222(26%) 261(30%) 87(10%) 93(11%) 52(6%) 67(8%) 10(1%) 13(1%) 13(2%) 18(2%) 130(15%) 157(18%) EDTA PLACEBO

SLIDE 7

E v e n t R a t e

0.0 0.1 0.2 0.3 0.4 0.5

M onths since random ization

6 12 18 24 30 36 42 48 54 60

H azard R atio 95% C I P -value E D T A :P lacebo 0.82 0.69,0.99 0.035

P lacebo E D TA C helation

N um ber at R isk ED TA C helation

839 760 703 650 588 537 511 476 427 358 229

Placebo

869 776 701 638 566 515 475 429 384 322 205

E v e n t 0 . 0 0 . 1 0 . 2 0 . 3 0 . 4 0 . 5 M o n t h s o f F o l l o w - u p 1 2 2 4 3 6 4 8 6 0 E v e n t 0 . 0 0 . 1 0 . 2 0 . 3 0 . 4 0 . 5 M o n t h s o f F o l l o w - u p 1 2 2 4 3 6 4 8 6 0 D i a b e t e s P L A C E B O ( 1 0 2 e v e n t s ) D i a b e t e s E D T A C H E L A T I O N ( 6 7 e v e n t s ) H R : 0 . 6 1 , 9 5 % C I : ( 0 . 4 5 , 0 . 8 3 ) p - v a l u e : 0 . 0 0 2 N o D i a b e t e s P L A C E B O ( 1 5 9 e v e n t s ) H R : 0 . 9 6 , 9 5 % C I : ( 0 . 7 7 , 1 . 2 0 ) p - v a l u e : 0 . 7 2 5 N o D i a b e t e s E D T A C H E L A T I O N ( 1 5 5 e v e n t s )

Primary Composite n=1708 Diabetics 31%

483 events : diff =39

169 events:diff =35

SLIDE 8

TACT: What We Need to Know

 Power to exclude chance given sample size, 18 vs 25%

RR , p value 0.035, wide 95% CI & 11 interim looks

 Rx interaction EDTA & high dose vitamins  Impact very long window of enrollment & trial interruption  Adequacy of f/up,compliance, retention & cross over issues  Comparability & adequacy of background EB Rx  Change in primary endpoint i.e add coronary revasc & drop

CHF (?More re safety esp. CHF, renal)

 Mechanism(s) of Rx benefit & logic subgroups esp. ant MI  Impact on quality life and functional status

SLIDE 9

TACT Reflections Nov 4 2012

 Diverse multi component intervention  Absence of clear biologic rationale  Several operational / methodologic issues  High % diabetics who dominate the effect  Coronary revasc principal driver :co- linear

with angina hospitalization in composite

 Hypothesis generating: not practice changing