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

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  Boehringer Ingelheim  sanofi aventis  Merck  Astra Zeneca  Eli Lilly  GlaxoSmithKline  Regado Biosciences  Consultant  Regado Biosciences  Data & Safety Monitoring Boards  Roche  Orexigen  Lilly 2012

Balancing TACT in Context Pro Con CT is likely unsafe, CT is valuable certainly ineffective effective & safe & should be abandoned Chappell & Jansen Ernst Birmingham Technology Assessment Group Report 2002

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

TACT: Primary Endpoint Results 0 .5 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 0 .4 a t e 483 events : intergp diff=39 E v e n t R 0 .3 P la c e b o E D T A C h e la tio n 0 .2 0 .1 Death, MI, stroke, coronary revascularization, hospitalization for angina 0 .0 0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 M o n th s s in c e ra n d o m iz a tio n N u m b er a t R isk 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 E D T A C h ela tio n 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 P la ceb o

TACT : Primary Endpoint Components EDTA PLACEBO HR (95%CI) Primary Endpoint 222(26%) 261(30%) 0.82(0.69-0.99) Death 87(10%) 93(11%) 0.93(0.70-1.25) Myocardial infarction 52(6%) 67(8%) 0.77(0.54-1.11) Stroke 10(1%) 13(1%) 0.77(0.34-1.76) Coronary revasc. 130(15%) 157(18%) 0.81(0.64-1.02) Hospitalization for angina 13(2%) 18(2%) 0.72(0.35-1.47) 0 1 2 EDTA Better Placebo Better

Primary Composite n=1708 Diabetics 31% 0.5 0 . 5 0 . 5 D i a b e t e s D i a b e t e s H R : 0 . 6 1 , 9 5 % C I : ( 0 . 4 5 , 0 . 8 3 ) N o D i a b e t e s N o D i a b e t e s H R : 0 . 9 6 , 9 5 % C I : ( 0 . 7 7 , 1 . 2 0 ) H azard R atio 95% C I P -value t t p - v a l u e : 0 . 0 0 2 p - v a l u e : 0 . 7 2 5 E D T A :P lacebo 0.82 0.69,0.99 0.035 169 events:diff =35 0.4 0 . 4 P L A C E B O ( 1 0 2 e v e n t s ) 0 . 4 P L A C E B O ( 1 5 9 e v e n t s ) t e 483 events : diff =39 n n E D T A C H E L A T I O N ( 6 7 e v e n t s ) E D T A C H E L A T I O N ( 1 5 5 e v e n t s ) a t R 0.3 e e 0 . 3 0 . 3 P lacebo E D TA C helation n e v 0.2 v v E 0 . 2 0 . 2 0.1 E E 0 . 1 0 . 1 0.0 0 6 12 18 24 30 36 42 48 54 60 0 . 0 0 . 0 M onths since random ization 0 1 2 2 4 3 6 4 8 6 0 0 1 2 2 4 3 6 4 8 6 0 M o n t h s o f F o l l o w - u p M o n t h s o f F o l l o w - u p N um ber at R isk 839 760 703 650 588 537 511 476 427 358 229 ED TA C helation 869 776 701 638 566 515 475 429 384 322 205 Placebo

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

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