A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels

Summary

The primary objective of this study is to determine the degree of additional reduction in cardiovascular risk that was accrued to patients by lowering their LDL-C beyond the currently accepted minimum target level for patients with pre-existing CHD. Secondary objectives include the safety profile of this treatment strategy, its cost-effectiveness, effect on other atherosclerotic-related events and procedures, and total mortality.

Timeline

Start

1998-04

Primary completion

—

Completion

2004-08

Outcome

Met primary endpoint

paper occurred in 10.9% of patients in the 10-mg and 8.7% of patients in the 80-mg group (P = .0002). PMID 19410683 ↗

Publications

• Results Waters DD, LaRosa JC, Barter P, Fruchart JC, Gotto AM Jr, Carter R, Breazna A, Kastelein JJ, Grundy SM. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J Am Coll Cardiol. 2006 Nov 7;48(9):1793-9. doi: 10.1016/j.jacc.2006.07.041. Epub 2006 Oct 17.
• Tunnicliffe DJ, Palmer SC, Cashmore BA, Saglimbene VM, Krishnasamy R, Lambert K, Johnson DW, Craig JC, Strippoli GF. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2023 Nov 29;11(11):CD007784. doi: 10.1002/14651858.CD007784.pub3.
• Vogt L, Bangalore S, Fayyad R, Melamed S, Hovingh GK, DeMicco DA, Waters DD. Atorvastatin Has a Dose-Dependent Beneficial Effect on Kidney Function and Associated Cardiovascular Outcomes: Post Hoc Analysis of 6 Double-Blind Randomized Controlled Trials. J Am Heart Assoc. 2019 May 7;8(9):e010827. doi: 10.1161/JAHA.118.010827.
• Bangalore S, Fayyad R, DeMicco DA, Colhoun HM, Waters DD. Body Weight Variability and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus. Circ Cardiovasc Qual Outcomes. 2018 Nov;11(11):e004724. doi: 10.1161/CIRCOUTCOMES.118.004724.
• Kaasenbrood L, Ray KK, Boekholdt SM, Smulders YM, LaRosa JC, Kastelein JJP, van der Graaf Y, Dorresteijn JAN, Visseren FLJ. Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease. Heart. 2018 Oct;104(20):1699-1705. doi: 10.1136/heartjnl-2017-312510. Epub 2018 Apr 5.
• Vallejo-Vaz AJ, Fayyad R, Boekholdt SM, Hovingh GK, Kastelein JJ, Melamed S, Barter P, Waters DD, Ray KK. Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial. Circulation. 2018 Aug 21;138(8):770-781. doi: 10.1161/CIRCULATIONAHA.117.032318.
• Ong KL, Waters DD, Fayyad R, Vogt L, Melamed S, DeMicco DA, Rye KA, Barter PJ. Relationship of High-Density Lipoprotein Cholesterol With Renal Function in Patients Treated With Atorvastatin. J Am Heart Assoc. 2018 Jan 22;7(2):e007387. doi: 10.1161/JAHA.117.007387.
• Ports WC, Fayyad R, DeMicco DA, Laskey R, Wolk R. Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis. Clin Drug Investig. 2017 Aug;37(8):775-785. doi: 10.1007/s40261-017-0533-0.
• Bangalore S, Fayyad R, Laskey R, DeMicco DA, Messerli FH, Waters DD. Body-Weight Fluctuations and Outcomes in Coronary Disease. N Engl J Med. 2017 Apr 6;376(14):1332-1340. doi: 10.1056/NEJMoa1606148.
• Stam-Slob MC, van der Graaf Y, Greving JP, Dorresteijn JA, Visseren FL. Cost-Effectiveness of Intensifying Lipid-Lowering Therapy With Statins Based on Individual Absolute Benefit in Coronary Artery Disease Patients. J Am Heart Assoc. 2017 Feb 18;6(2):e004648. doi: 10.1161/JAHA.116.004648.
• Deedwania PC, Pedersen TR, DeMicco DA, Breazna A, Betteridge DJ, Hitman GA, Durrington P, Neil A; TNT, CARDS and IDEAL Steering Committees and Investigators. Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes. Int J Cardiol. 2016 Nov 1;222:548-556. doi: 10.1016/j.ijcard.2016.07.201. Epub 2016 Jul 30.
• Byun YS, Lee JH, Arsenault BJ, Yang X, Bao W, DeMicco D, Laskey R, Witztum JL, Tsimikas S; TNT Trial Investigators. Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial. J Am Coll Cardiol. 2015 Apr 7;65(13):1286-1295. doi: 10.1016/j.jacc.2015.01.050.
• Arsenault BJ, Barter P, DeMicco DA, Bao W, Preston GM, LaRosa JC, Grundy SM, Deedwania P, Greten H, Wenger NK, Shepherd J, Waters DD, Kastelein JJ; Treating to New Targets (TNT) Investigators. Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers. PLoS One. 2014 Dec 22;9(12):e114519. doi: 10.1371/journal.pone.0114519. eCollection 2014.
• Dorresteijn JA, Boekholdt SM, van der Graaf Y, Kastelein JJ, LaRosa JC, Pedersen TR, DeMicco DA, Ridker PM, Cook NR, Visseren FL. High-dose statin therapy in patients with stable coronary artery disease: treating the right patients based on individualized prediction of treatment effect. Circulation. 2013 Jun 25;127(25):2485-93. doi: 10.1161/CIRCULATIONAHA.112.000712. Epub 2013 May 14.
• Semb AG, Kvien TK, DeMicco DA, Fayyad R, Wun CC, LaRosa JC, Betteridge J, Pedersen TR, Holme I. Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease. Arthritis Rheum. 2012 Sep;64(9):2836-46. doi: 10.1002/art.34524.
• Huijgen R, Boekholdt SM, Arsenault BJ, Bao W, Davaine JM, Tabet F, Petrides F, Rye KA, DeMicco DA, Barter PJ, Kastelein JJ, Lambert G. Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) trial: a nested case-control study. J Am Coll Cardiol. 2012 May 15;59(20):1778-84. doi: 10.1016/j.jacc.2011.12.043.
• Mora S, Wenger NK, Demicco DA, Breazna A, Boekholdt SM, Arsenault BJ, Deedwania P, Kastelein JJ, Waters DD. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study. Circulation. 2012 Apr 24;125(16):1979-87. doi: 10.1161/CIRCULATIONAHA.111.088591. Epub 2012 Mar 29.
• Arsenault BJ, Boekholdt SM, Hovingh GK, Hyde CL, DeMicco DA, Chatterjee A, Barter P, Deedwania P, Waters DD, LaRosa JC, Pedersen TR, Kastelein JJ; TNT and IDEAL Investigators. The 719Arg variant of KIF6 and cardiovascular outcomes in statin-treated, stable coronary patients of the treating to new targets and incremental decrease in end points through aggressive lipid-lowering prospective studies. Circ Cardiovasc Genet. 2012 Feb 1;5(1):51-7. doi: 10.1161/CIRCGENETICS.111.960252. Epub 2011 Dec 1.
• Arsenault BJ, Barter P, DeMicco DA, Bao W, Preston GM, LaRosa JC, Grundy SM, Deedwania P, Greten H, Wenger NK, Shepherd J, Waters DD, Kastelein JJ; TNT Study Investigators. Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers. J Am Coll Cardiol. 2011 Jan 4;57(1):63-9. doi: 10.1016/j.jacc.2010.06.052.
• Hyde CL, Macinnes A, Sanders FA, Thompson JF, Mazzarella RA, Faergeman O, van Wijk DF, Wood L, Lira M, Paciga SA. Genetic association of the CCR5 region with lipid levels in at-risk cardiovascular patients. Circ Cardiovasc Genet. 2010 Apr;3(2):162-8. doi: 10.1161/CIRCGENETICS.109.897793. Epub 2010 Feb 3.
• Waters DD. Clinical insights from the Treating to New Targets trial. Prog Cardiovasc Dis. 2009 May-Jun;51(6):487-502. doi: 10.1016/j.pcad.2009.01.001.
• Shepherd J, Kastelein JP, Bittner VA, Carmena R, Deedwania PC, Breazna A, Dobson S, Wilson DJ, Zuckerman AL, Wenger NK; Treating to New Targets Steering Committee and Investigators. Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease. Mayo Clin Proc. 2008 Aug;83(8):870-9.
• Shah SJ, Waters DD, Barter P, Kastelein JJ, Shepherd J, Wenger NK, DeMicco DA, Breazna A, LaRosa JC. Intensive lipid-lowering with atorvastatin for secondary prevention in patients after coronary artery bypass surgery. J Am Coll Cardiol. 2008 May 20;51(20):1938-43. doi: 10.1016/j.jacc.2007.12.054.
• Shepherd J, Kastelein JJ, Bittner V, Deedwania P, Breazna A, Dobson S, Wilson DJ, Zuckerman A, Wenger NK; TNT (Treating to New Targets) Investigators. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol. 2008 Apr 15;51(15):1448-54. doi: 10.1016/j.jacc.2007.11.072.
• Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007 Sep 27;357(13):1301-10. doi: 10.1056/NEJMoa064278.

Drugs

Indications