Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: The dal-VESSEL randomized clinical trial

European Heart Journal

Volumn 33, Issue 7, 2012, Pages

  Lüscher, Thomas F ^a   Taddei, Stefano ^b   Kaski, Juan Carlos ^c   Jukema, J Wouter ^d   Kallend, David ^e   Münzel, Thomas ^f   Kastelein, John J P ^g   Deanfield, John E ^h  

^a UNIVERSITY OF ZURICH   (Switzerland)

^b UNIVERSITY OF PISA   (Italy)

^c ST GEORGE'S UNIVERSITY OF LONDON   (United Kingdom)

^d LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^e JOHANNES GUTENBERG UNIVERSITY   (Germany)

^f ACADEMIC MEDICAL CENTER   (Netherlands)

^g F HOFFMANN LA ROCHE LTD   (Switzerland)

^h UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

Cholesterol (HDL C); Dalcetrapib; High density; Lipoprotein; Torcetrapib

Indexed keywords

BIOLOGICAL MARKER; DALCETRAPIB; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PHOSPHOLIPASE A2; PLACEBO;

ADULT; ARTICLE; BACKACHE; BLOOD FLOW VELOCITY; BLOOD PRESSURE MONITORING; BRACHIAL ARTERY; CARDIOVASCULAR RISK; CONTROLLED STUDY; DIARRHEA; DOUBLE BLIND PROCEDURE; DRUG ACTIVITY; DRUG EFFECT; DRUG SAFETY; FEMALE; FOLLOW UP; HEADACHE; HUMAN; INFLAMMATION; INFLUENZA; ISCHEMIC HEART DISEASE; LABORATORY TEST; LIPID ANALYSIS; MAJOR CLINICAL STUDY; MALE; OXIDATIVE STRESS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RHINOPHARYNGITIS; TREATMENT OUTCOME;

AGED; ANTICHOLESTEREMIC AGENTS; BIOLOGICAL MARKERS; BLOOD FLOW VELOCITY; BLOOD PRESSURE; BRACHIAL ARTERY; CHOLESTEROL ESTER TRANSFER PROTEINS; CHOLESTEROL, HDL; CHOLESTEROL, LDL; CORONARY DISEASE; DOUBLE-BLIND METHOD; ENDOTHELIUM, VASCULAR; FEMALE; HUMANS; HYPERCHOLESTEROLEMIA; MALE; MIDDLE AGED; SULFHYDRYL COMPOUNDS; TREATMENT OUTCOME; TRIGLYCERIDES; VASODILATION;

EID: 84859517252     PISSN: 0195668X     EISSN: 15229645     Source Type: Journal    
DOI: 10.1093/eurheartj/ehs019     Document Type: Article

References (53)

1. Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, PatschW. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108-1113. (Pubitemid 32830392)
2. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423.
3. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-1278.
4. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310. (Pubitemid 47481452)
5. Le Goff W, Guerin M, Chapman MJ. Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyslipidemia. Pharmacol Ther 2004;101:17-38. (Pubitemid 38068523)
6. Clark RW, Ruggeri RB, Cunningham D, Bamberger MJ. Description of the torcetrapib series of cholesteryl ester transfer protein inhibitors, including mechanism of action. J Lipid Res 2006;47:537-552. (Pubitemid 43345595)
7. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-2122. (Pubitemid 350146106)
8. Hu X, Dietz JD, Xia C, Knight DR, Loging WT, Smith AH, Yuan H, Perry DA, Keiser J. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology 2009;150:2211-2219.
9. Stroes ES, Kastelein JJ, Benardeau A, Kuhlmann O, Blum D, Campos LA, Clerc RG, Niesor EJ. Dalcetrapib: no off-target toxicity on blood pressure or on genes related to the renin-angiotensin-aldosterone system in rats. Br J Pharmacol 2009;158:1763-1770.
10. Clerc RG, Stauffer A, Weibel F, Hainaut E, Perez A, Hoflack JC, Benardeau A, Pflieger P, Garriz JM, Funder JW, Capponi AM, Niesor EJ. Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens 2010;28:1676-1686.
11. Simic B, Hermann M, Shaw SG, Bigler L, Stalder U, Dorries C, Besler C, Luscher TF, Ruschitzka F. Torcetrapib impairs endothelial function in hypertension. Eur Heart J; doi:10.1093/eurheartj/ehr348. Published online ahead of print 14 September 2011.
12. Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, Marcel YL, Anderson RG, Mendelsohn ME, Hobbs HH, Shaul PW. High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat Med 2001;7:853-857. (Pubitemid 32691642)
13. Drew BG, Fidge NH, Gallon-Beaumier G, Kemp BE, Kingwell BA. High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation. Proc Natl Acad Sci USA 2004;101:6999-7004. (Pubitemid 38596432)
14. Mineo C, Yuhanna IS, Quon MJ, Shaul PW. High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases. J Biol Chem 2003;278:9142-9149. (Pubitemid 36800395)
15. Kuvin JT, Ramet ME, Patel AR, Pandian NG, Mendelsohn ME, Karas RH. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J 2002;144:165-172. (Pubitemid 34734771)
16. Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, Chroni A, Yonekawa K, Stein S, Schaefer N, Mueller M, Akhmedov A, Daniil G, Manes C, Templin C, Wyss C, Maier W, Tanner FC, Matter CM, Corti R, Furlong C, Lusis AJ, von Eckardstein A, Fogelman AM, Luscher TF, Landmesser U. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 2011;121:2693-2708.
17. Spieker LE, Sudano I, Hurlimann D, Lerch PG, Lang MG, Binggeli C, Corti R, Ruschitzka F, Luscher TF, Noll G. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 2002;105:1399-1402. (Pubitemid 34263266)
18. Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, Hershey JC, Keller WJ, Ma X, McPherson HE, Messina E, Peterson LB, Sharif-Rodriguez W, Siegl PK, Sinclair PJ, Sparrow CP, Stevenson AS, Sun SY, Tsai C, Vargas H, Walker M 3rd, West SH, White V, Woltmann RF. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008;154:1465-1473.
19. Stein EA, Roth EM, Rhyne JM, Burgess T, Kallend D, Robinson JG. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial. Eur Heart J 2010;31:480-488.
20. Niesor EJ, Magg C, Ogawa N, Okamoto H, von der Mark E, Matile H, Schmid G, Clerc RG, Chaput E, Blum-Kaelin D, Huber W, Thoma R, Pflieger P, Kakutani M, Takahashi D, Dernick G, Maugeais C. Modulating cholesteryl ester transfer protein activity maintains efficient pre-beta-HDL formation and increases reverse cholesterol transport. J Lipid Res 2010;51:3443-3454.
21. Kastelein JJ, Duivenvoorden R, Deanfield J, de Groot E, Jukema JW, Kaski JC, Munzel T, Taddei S, Lehnert V, Burgess T, Kallend D, Luscher TF. Rationale and design of dal-VESSEL: a study to assess the safety and efficacy of dalcetrapib on endothelial function using brachial artery flow-mediated vasodilatation. Curr Med Res Opin 2011;27:141-150.
22. Hermann F, Enseleit F, Spieker LE, Periat D, Sudano I, Hermann M, Corti R, Noll G, Ruschitzka F, Luscher TF. Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia. Thromb Res 2009;123:460-465.
23. Stein EA, Stroes ES, Steiner G, Buckley BM, Capponi AM, Burgess T, Niesor EJ, Kallend D, Kastelein JJ. Safety and tolerability of dalcetrapib. Am J Cardiol 2009;104:82-91.
24. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-2497.
25. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111-1115.
26. Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ. Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005;23:7-17. (Pubitemid 40128972)
27. Schwartz GG, Olsson AG, Ballantyne CM, Barter PJ, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Shah PK, Tardif JC, Chaitman BR, Duttlinger-Maddux R, Mathieson J. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009;158:896-901 e893.
28. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-714. (Pubitemid 8110784)
29. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15.
30. Nicholls SJ, Dusting GJ, Cutri B, Bao S, Drummond GR, Rye KA, Barter PJ. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation 2005;111:1543-1550. (Pubitemid 40470651)
31. Ansell BJ, Navab M, Hama S, Kamranpour N, Fonarow G, Hough G, Rahmani S, Mottahedeh R, Dave R, Reddy ST, Fogelman AM. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 2003;108:2751-2756. (Pubitemid 37498976)
32. Viswambharan H, Ming XF, Zhu S, Hubsch A, Lerch P, Vergeres G, Rusconi S, Yang Z. Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase. Circ Res 2004;94:918-925. (Pubitemid 38490069)
33. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, Halpern S, Crowe T, Blankenship JC, Kerensky R. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-2300. (Pubitemid 37430562)
34. Anderson TJ, Gerhard MD, Meredith IT, Charbonneau F, Delagrange D, Creager MA, Selwyn AP, Ganz P. Systemic nature of endothelial dysfunction in atherosclerosis. Am J Cardiol 1995;75:71B-74B.
35. Kinlay S, Ganz P. Role of endothelial dysfunction in coronary artery disease and implications for therapy. Am J Cardiol 1997;80:11I-16I. (Pubitemid 27490822)
36. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation 2002;105:2159-2165. (Pubitemid 34517159)
37. Kuivenhoven JA, de Grooth GJ, Kawamura H, Klerkx AH, Wilhelm F, Trip MD, Kastelein JJ. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol 2005;95:1085-1088. (Pubitemid 40544314)
38. Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, Shear CL, Duggan WT, Vicari RM, Grobbee DE, Kastelein JJ. Torcetrapib and carotid intimamedia thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007;370:153-160. (Pubitemid 47042895)
39. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304-1316. (Pubitemid 46513296)
40. Blasi E, Bamberger M, Knight D, Engwall M, Wolk R, Winter S, Betts A, John-Baptiste A, Keiser J. Effects of CP-532,623 and torcetrapib, cholesteryl ester transfer protein inhibitors, on arterial blood pressure. J Cardiovasc Pharmacol 2009;53:507-516.
41. DePasquale M, Cadelina G, Knight D, Loging W, Winter S, Blasi E, Perry D, Keiser J. Mechanistic studies of blood pressure in rats treated with a series of cholesteryl ester transfer protein inhibitors. Drug Dev Res 2009;70:35-48.
42. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB, Zafarino J, Mitchel Y, Barter P. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-2415.
43. Niesor EJ. Different effects of compounds decreasing cholesteryl ester transfer protein activity on lipoprotein metabolism. Curr Opin Lipidol 2011;22:288-295.
44. Mullen MJ, Thorne SA, Deanfield JE, Jones CJ. Non-invasive assessment of endothelial function. Heart 1997;77:297-298.
45. Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003;41:1769-1775. (Pubitemid 36584251)
46. Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106:653-658. (Pubitemid 34851922)
47. Juonala M, Viikari JS, Laitinen T, Marniemi J, Helenius H, Ronnemaa T, Raitakari OT. Interrelations between brachial endothelial function and carotid intima-media thickness in young adults: the cardiovascular risk in young Finns study. Circulation 2004;110:2918-2923. (Pubitemid 39473618)
48. Stapleton PA, Goodwill AG, James ME, Brock RW, Frisbee JC. Hypercholesterolemia and microvascular dysfunction: interventional strategies. J Inflamm (Lond) 2010;7:54.
49. Sorrentino SA, Besler C, Rohrer L, Meyer M, Heinrich K, Bahlmann FH, Mueller M, Horvath T, Doerries C, Heinemann M, Flemmer S, Markowski A, Manes C, Bahr MJ, Haller H, von Eckardstein A, Drexler H, Landmesser U. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 2010;121:110-122.
50. Herrington DM, Espeland MA, Crouse JR 3rd, Robertson J, Riley WA, McBurnie MA, Burke GL. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol 2001;21:1955-1961. (Pubitemid 34219747)
51. Kelemen M, Vaidya D, Waters DD, Howard BV, Cobb F, Younes N, Tripputti M, Ouyang P. Hormone therapy and antioxidant vitamins do not improve endothelial vasodilator function in postmenopausal women with established coronary artery disease: a substudy of the Women's Angiographic Vitamin and Estrogen (WAVE) trial. Atherosclerosis 2005;179:193-200. (Pubitemid 40249803)
52. Stein JH, Carlsson CM, Papcke-Benson K, Aeschlimann SE, Bodemer A, Carnes M, McBride PE. The effects of lipid-lowering and antioxidant vitamin therapies on flow-mediated vasodilation of the brachial artery in older adults with hypercholesterolemia. J Am Coll Cardiol 2001;38:1806-1813. (Pubitemid 33116548)
53. Charakida M, Besler C, Batuca JR, Sangle S, Marques S, Sousa M, Wang G, Tousoulis D, Delgado Alves J, Loukogeorgakis SP, Mackworth-Young C, D'Cruz D, Luscher T, Landmesser U, Deanfield JE. Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome. JAMA 2009;302:1210-1217.