The Stabilization Of pLaques usIng Darapladib (SOLID)-TIMI 52 trial: Primary Results Michelle L. O’Donoghue MD MPH, on behalf of the SOLID-TIMI 52 investigators European Society of Cardiology Congress Barcelona, Spain Sunday August 31, 2014
Lipoprotein- associated Phospholipase A 2 (Lp-PLA 2 ) activity: Background native LDL Lp-PLA 2 Leukocyte carrier of Lp-PLA 2 Lumen Atheroma Sustained Inflammation Intima Lp-PLA 2 Necrotic Core Expansion Oxidized LDL substrate for Lp-PLA 2 Macphee, Biochem J 1999; Zalewski and Macphee, ATVB 2005; Shi Atherosclerosis 2007; Kolodgie, ATVB 2006
Lp-PLA 2 activity and risk of CV outcomes: shape of association 79,036 participants, 32 prospective studies All vascular death Coronary heart disease* Vascular Death Coronary Heart Disease* 2.5 2.5 2965 events, 13 studies 5221 events, 17 studies 2.0 2.0 Risk ratio (95% CI) 1.5 1.5 1.0 1.0 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 Standardized Lp-PLA 2 activity Standardized Lp-PLA 2 activity Lp-PLA 2 Studies Collaboration. Lancet 2010;375:1536-44 Adjusted for age, sex, diabetes and baseline history of vascular disease
Darapladib – Phase 2 Results IBIS-2 Trial 330 patients with angiographic CAD Change in necrotic core volume Change in necrotic core, 5 at follow-up % of total plaque 6 mm 3 . change from baseline 4 Change from baseline (%) Placebo P=0.047 4 P=0.012 p = 0.006, versus 3 baseline Darapladib 2 Darapladib +4.5mm 3 p = 0.45, 2 +2.5% versus Placebo baseline -0.5mm 3 0 1 p = 0.71, p = 0.009, +0.5% versus versus -2 baseline baseline 0 No significant change in: Plaque deformability - Primary endpoint C-reactive protein - Atheroma volume - Serruys et al., Circulation 2008;118:1172-1182.
Darapladib Phase III Clinical Program High risk* patients with High risk* patients ACS (STEMI, NSTEMI, UA) with chronic CHD Randomization to Randomization to Darapladib or Placebo within Darapladib or Placebo 30 days of index event n= 15,898 n= 13,026 (3.7 year median f/u) (2.5 year median f/u) * High-risk criteria ( ≥1 of the following): age >60 years, diabetes mellitus, (eGFR 30-60 ml/min/1.73 m 2 ), polyvascular disease, HDL <40 mg/dl (STABILITY only), tobacco use (STABILITY only), or prior MI (SOLID-TIMI 52 only)
STABILITY Trial 15,828 patients with stable CHD randomized to darapladib 160mg QD vs placebo HR (95% CI) Primary Endpoint CV death, MI or stroke 0.94 (0.85-1.03) P=0.20 Selected Secondary Endpoints Major Coronary Events: (CHD death, MI or urgent coronary 0.90 (0.82-1.00) P=0.045 revascularization for myocardial ischemia) Total Coronary Events (CHD death, MI, hospitalization for UA or 0.91 (0.84-0.98) P=0.02 any coronary revascularization) 0.6 0.7 0.8 0.9 1.0 1.2 1.6 Favors darapladib Favors placebo White et al., N Engl J Med 2014; 370:1702-11.
SOLID-TIMI 52 Primary Trial Objective To demonstrate that the addition of darapladib to a background of optimal medical therapy would significantly reduce the risk of major coronary events in patients after an ACS.
Trial Organization Trial Leadership: TIMI Study Group Eugene Braunwald (Chair) Suzanne Morin (Director of Operations) Christopher P. Cannon (Global PI) Sabina A. Murphy (Statistics) Michelle L. O’Donoghue (Co-PI) Kyungah Im (Statistics) Dylan P. Steen (Co-Investigator) Stephen D. Wiviott (CEC Chair) Sharon Crugnale (Senior Project Director) Marc P. Bonaca (SAE Chair) Executive Committee Eugene Braunwald Christoph Bode Christopher P. Cannon Judith S. Hochman P. Gabriel Steg Patrick W. Serruys Aldo P. Maggioni W. Douglas Weaver Harvey D. White Sponsor (GlaxoSmithKline) Elizabeth Tarka Richard Y. Davies Mary Ann Lukas Jennifer B. Shannon David F. Watson Katharine Edmonds Shruti Daga Independent Data Monitoring Committee Rory Collins (Chair) David DeMets Jeffrey Anderson Peter Sandercock Peter Ganz Michael Weber
National Lead Investigators ARGENTINA ( 159 ) GERMANY ( 510 ) ROMANIA ( 246 ) Ernesto Paolasso Christian Hamm Maria Dorobantu AUSTRALIA ( 210 ) GREECE RUSSIA ( 876 ) Phil Aylward John Lekakis Nikolay Gratsiansky BELGIUM ( 139 ) HUNGARY ( 350 ) SLOVAKIA ( 203 ) William Wijns Robert Kiss Tibor Duris BRAZIL ( 415 ) INDIA ( 345 ) SOUTH AFRICA ( 297 ) Atul Mathur/Krishna Reddy/ Jose Carlos Nicolau Anthony Dalby Sanjay Mittal/B. Soma Raju BULGARIA ( 284 ) ISRAEL ( 690 ) SPAIN ( 165 ) Assen Goudev Basil Lewis Jose Lopez-Sendon CANADA ( 327 ) ITALY( 229 ) SWEDEN ( 157 ) Pierre Theroux Diego Ardissino Mikael Dellborg G.B. John Mancini CHILE ( 155 ) JAPAN ( 211 ) TAIWAN( 132 ) Ramon Corbalan Takeshi Kimura Shih-Ann Chen CHINA ( 444 ) KOREA ( 119 ) THAILAND ( 114 ) Runlin Gao Ki-Bae Seung Piyamatr Sritara COLOMBIA ( 173 ) MEXICO TURKEY( 9 ) Daniel Isaza Guillermo Llamas Esperon Sema Guneri CZECH REPUBLIC ( 443 ) NETHERLANDS ( 622 ) UNITED KINGDOM ( 167 ) Jindrich Spinar Ton Oude-Ophuis/R.J. DeWinter Kausik Ray DENMARK ( 442 ) NEW ZEALAND ( 120 ) UKRAINE ( 306 ) Steen Husted Harvey White Alexander Parkhomenko ESTONIA PHILIPPINES ( 110 ) UNITED STATES ( 2476 ) Juri Voitk Noe Babilonia Christopher P . Cannon FRANCE ( 270 ) POLAND ( 1056 ) Gilles Montalescot Andrzej Budaj 36 Countries 868 Sites
SOLID-TIMI 52 Study Design High-risk* patients ≤30 days post -ACS: UA, NSTEMI or STEMI * Must have met ≥ 1 enrichment criteria -Age ≥60y Total N 13,026 -DM req Rx Guideline-recommended background Rx, -Polyvascular disease including statins and antiplatelet drugs -Prior MI -eGFR 30-59 ml/min/1.73m 2 Randomized 1:1 Darapladib Placebo Double-blind (daily) (160mg daily) Median f/u 2.5y Primary Endpoint: CHD Death, Non-fatal MI, or Urgent Coronary Revascularization for Myocardial Ischemia
Enrollment Enrolled 12/2009 - 11/2011: 36 countries, 868 sites, 13026 patients Sweden: 157 Denmark: 442 Ukraine: 306 Russia: 876 Netherlands: 622 Canada: Romania: 246 327 U.K. 168 Czech Rep: 443 Slovakia: 203 Poland: 1056 Hungary: 350 United States Belgium: 138 Bulgaria: 284 S Korea: 119 Japan: 211 2479 Turkey: 9 Germany: 510 China: 445 France: 270 Taiwan: 130 Israel: 690 Thailand: 114 Spain: 166 Philippines: 110 Colombia: 172 India: 345 Italy: 229 Brazil: 414 Peru: 55 Chile: 155 Australia: 209 Argentina: 159 South Africa: 296 New Zealand: 121
Baseline Characteristics Characteristic Placebo Darapladib (n=6522) (n=6504) Age (median, IQR) 64 (59-71) 64 (59-70) Female 26% 25% White race 84% 84% BMI (kg/m 2 , median, IQR) 28 (25-31) 28 (25-31) Current smoker 19% 19% Diabetes mellitus req Rx 30% 30% Prior MI 31% 31% Index event STEMI 44% 46% NSTEMI 44% 42% UA 12% 12% Catheterization for QE 86% 86% PCI performed for QE 77% 77% Days from QE to rando 14 (6-23) 15 (6-23) (median, IQR) QE= qualifying event; IQR= interquartile range; PCI= percutaneous coronary intervention
Baseline Data Characteristic Placebo Darapladib (n=6522) (n=6504) LDL cholesterol 75 (57-97) 75 (57-97) [1.9 (1.5-2.5) mM] [1.9 (1.5-2.5) mM] (mg/dl, median, IQR) HDL cholesterol 42 (36-50) 42 (36-50) [1.1 (0.9-1.3) mM] [1.1 (0.9-1.3) mM] (mg/dl, median, IQR) Triglycerides 134 (100-183) 135 (101-182) [1.5 (1.1-2.1) mM] [1.5 (1.1-2.1) mM] (mg/dl, median, IQR) Baseline medications Aspirin 96% 96% Statin 95% 94% Beta blocker 87% 87% P2Y 12 inhibitor 88% 88% ACE inhibitor or ARB 82% 83% IQR=interquartile range
Trial Retention Metrics Placebo Darapladib Overall (n=6,522) (n=6,504) (n=13,026) Premature study 1546 1854 3400 drug discontinuation (9.5% per yr) (11.4% per yr) (10.4% per yr) Withdrawn consent 111 (1.7%) 109 (1.7%) 220 (1.7%) VS known 96 90 186 VS unknown 15 19 34 Lost to Follow Up VS known 34 37 71 VS unknown 7 6 13 Vital status at end of study was known in 99.6% of subjects. There were 31,167 total patient-years of follow-up. VS=vital status
Primary Endpoint: CHD death, MI or urgent coronary revascularization 18% Placebo 16% Darapladib 14% 12% Event rate 10% 8% HR 1.00 (95% CI 0.91-1.09) P=0.93 6% 4% 2% 0% 0 3 6 9 12 15 18 21 24 27 30 33 36 Months No. at risk Placebo 6522 6219 6060 5945 5825 5726 5638 5544 5046 3942 2684 1550 669 Darapladib 6504 6201 6038 5902 5787 5708 5636 5534 5061 3955 2673 1558 634
CV death, MI or stroke 18% Placebo 16% Darapladib 14% 12% Event Rate 10% 8% HR 0.99 (95% CI 0.90-1.09) P=0.78 6% 4% 2% 0% 0 3 6 9 12 15 18 21 24 27 30 33 36 Months No. at risk Placebo 6522 6249 6118 6021 5911 5818 5732 5640 5142 4031 2747 1587 678 Darapladib 6504 6238 6100 5987 5881 5805 5746 5636 5152 4018 2723 1584 644
Total coronary events (CHD death, MI, UA or any coronary revascularization) 25% Placebo Darapladib 20% 15% Event Rate HR 0.95 (95% CI 0.88-1.03) 10% P=0.20 5% 0% 0 3 6 9 12 15 18 21 24 27 30 33 36 Months No. at risk Placebo 6504 6100 5852 5657 5504 5384 5294 5180 4729 3678 2485 1444 584 Darapladib 6522 6102 5846 5654 5495 5356 5249 5137 4666 3637 2467 1418 606
Components of Primary Endpoint Outcome HR (95% CI) P value Primary endpoint: Major coronary events (CHD death, MI or urgent 1.00 (0.91-1.09) 0.93 coronary revascularization for myocardial ischemia) CHD death 0.88 (0.73-1.05) 0.16 MI (fatal and non-fatal) 0.97 (0.86-1.09) 0.63 Urgent coronary revascularization for myocardial 1.09 (0.91-1.31) 0.36 ischemia
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