Advertisement

Surrogate markers in clinical trials—Challenges and opportunities

      Abstract

      Surrogate markers have recently come under scrutiny since a few of the considered most reliable intermediate endpoints (LDL-c, HDL-c and HbA1c) have failed to predict clinical benefit following pharmacological intervention in the causal pathway. However, it follows that comprehending the pathophysiological complexity of atherosclerotic vascular disease, no single surrogate is likely to be omniscient in the translation of benefit or harm of a certain therapy. Especially surrogates that are assessed in the circulation merely reflect a part of the complex multipathway disease. Such markers do not have the ability to monitor potential side effects of interventions or assess the activation of unknown pro-atherogenic pathways. Contrary to such soluble endpoints, vascular imaging data can provide information on atherosclerosis as a continuous variable, since the disease process of the vascular wall itself is assessed. Understanding this continuity from the earliest stages through to the vascular complications is essential, as the arterial wall reflects the net effect of either known or yet to be discovered hereditary as well as environmental factors.
      In this review we will focus on challenges and pitfalls using plasma biomarkers as surrogate endpoints for the assessment of cardiovascular drug efficacy. Subsequently, we will focus on vascular imaging modalities as tools to investigate atherosclerosis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      Reference

        • Tavridou A.
        • Manolopoulos V.G.
        Novel molecules targeting dyslipidemia and atherosclerosis.
        Curr Med Chem. 2008; 15: 792-802
        • Krumholz H.M.
        • Lee T.H.
        Redefining quality-implications of recent clinical trials.
        N Engl J Med. 2008; 358: 2537-2539
        • NIH Definition Working Group
        Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.
        Clin Pharmacol Ther. 2001; 69: 89-95
        • Boissel J.P.
        • Collet J.P.
        • Moleur P.
        • Haugh M.
        Surrogate endpoints: a basis for a rational approach.
        Eur J Clin Pharmacol. 1992; 43: 235-244
        • Smilde T.J.
        • Wollersheim H.
        • Van L.H.
        • Stalenhoef A.F.
        Reproducibility of ultrasonographic measurements of different carotid and femoral artery segments in healthy subjects and in patients with increased intima-media thickness.
        Clin Sci (Lond). 1997; 93: 317-324
        • Hansson G.K.
        • Inflammation
        atherosclerosis, and coronary artery disease.
        N Engl J Med. 2005; 352: 1685-1695
        • Kannel W.B.
        • Castelli W.P.
        • Gordon T.
        Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study.
        Ann Intern Med. 1979; 90: 85-91
        • Castelli W.P.
        Cholesterol and lipids in the risk of coronary artery disease—the Framingham Heart Study.
        Can J Cardiol. 1988; 4: 5A-10A
        • Law M.R.
        • Wald N.J.
        • Rudnicka A.R.
        Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
        BMJ. 2003; 326: 1423
        • Rossouw J.E.
        • Anderson G.L.
        • Prentice R.L.
        • et al.
        Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women's health initiative randomized controlled trial.
        JAMA. 2002; 288: 321-333
        • Kastelein J.J.
        • Akdim F.
        • Stroes E.S.
        • et al.
        Simvastatin with or without ezetimibe in familial hypercholesterolemia.
        N Engl J Med. 2008; 358: 1431-1443
        • Stein E.A.
        After ENHANCE: is more LDL cholesterol lowering even better?.
        Clin Chem. 2008; 54: 940-942
        • Smilde T.J.
        • van W.S.
        • Wollersheim H.
        • Trip M.D.
        • Kastelein J.J.
        • Stalenhoef A.F.
        Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial.
        Lancet. 2001; 357: 577-581
        • Gordon D.J.
        • Probstfield J.L.
        • Garrison R.J.
        • et al.
        High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.
        Circulation. 1989; 79: 8-15
        • Canner P.L.
        • Berge K.G.
        • Wenger N.K.
        • et al.
        Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
        J Am Coll Cardiol. 1986; 8: 1245-1255
        • Birjmohun R.S.
        • Hutten B.A.
        • Kastelein J.J.P.
        • et al.
        Increasing HDL cholesterol with extended release nicotinic acid: from promise to practice.
        Neth J Med. 2004; 62: 229-234
        • Barter P.J.
        • Caulfield M.
        • Eriksson M.
        • et al.
        Effects of torcetrapib in patients at high risk for coronary events.
        N Engl J Med. 2007; 357: 2109-2122
      1. Vergeer M, Bots ML, van Leuven SI, et al. The CETP inhibitor torcetrapib and off-target toxicity: a pooled analysis of the RADIANCE trials. Circulation; in press.

        • Forrest M.J.
        • Bloomfield D.
        • Briscoe R.J.
        • et al.
        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
        • Stroes E.S.
        • Kastelein J.J.
        • Bernardeau A.
        Absence of effect of R1658/JTT-705 on blood pressure and tissue expression of renin-angiotensin system related genes in rats.
        J Am College Cardiol. 2008; 51: A322
        • Selvin E.
        • Marinopoulos S.
        • Berkenblit G.
        • et al.
        Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus.
        Ann Intern Med. 2004; 141: 421-431
        • Gerstein H.C.
        • Miller M.E.
        • Byington R.P.
        • et al.
        Effects of intensive glucose lowering in type 2 diabetes.
        N Engl J Med. 2008; 358: 2545-2559
        • Kahn S.E.
        • Haffner S.M.
        • Heise M.A.
        • et al.
        Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
        N Engl J Med. 2006; 355: 2427-2443
        • Nissen S.E.
        • Wolski K.
        Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
        N Engl J Med. 2007; 356: 2457-2471
        • Rosen C.J.
        The rosiglitazone story—lessons from an FDA advisory committee meeting.
        N Engl J Med. 2008; 357: 844-845
        • Tobis J.M.
        • Mallery J.
        • Mahon D.
        • et al.
        Intravascular ultrasound imaging of human coronary arteries in vivo. Analysis of tissue characterizations with comparison to in vitro histological specimens.
        Circulation. 1991; 83: 913-926
        • Mintz G.S.
        • Nissen S.E.
        • Anderson W.D.
        • et al.
        American College of Cardiology Clinical Expert Consensus Document on Standards for acquisition, Measurement and Reporting of intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.
        J Am Coll Cardiol. 2001; 37: 1478-1492
        • Nissen S.E.
        • Tuzcu E.M.
        • Schoenhagen P.
        • et al.
        Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
        JAMA. 2004; 291: 1071-1080
        • Taylor A.J.
        • Kent S.M.
        • Flaherty P.J.
        • Coyle L.C.
        • Markwood T.T.
        • Vernalis M.N.
        ARBITER: arterial biology for the investigation of the treatment effects of reducing cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness.
        Circulation. 2002; 106: 2055-2060
        • Nissen S.E.
        • Nicholls S.J.
        • Sipahi I.
        • et al.
        Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.
        JAMA. 2006; 295: 1556-1565
        • Nissen S.E.
        • Tardif J.C.
        • Nicholls S.J.
        • et al.
        Effect of torcetrapib on the progression of coronary atherosclerosis.
        N Engl J Med. 2007; 356: 1304-1316
        • Kastelein J.J.
        • van Leuven S.I.
        • Burgess L.
        • et al.
        Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia.
        N Engl J Med. 2007; 356: 1620-1630
        • Bots M.L.
        • Visseren F.L.
        • Evans G.W.
        • et al.
        Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial.
        Lancet. 2007; 370: 153-160
        • Nicholls S.J.
        • Sipahi I.
        • Schoenhagen P.
        • et al.
        Intravascular ultrasound assessment of novel antiatherosclerotic therapies: rationale and design of the Acyl-CoA:Cholesterol Acyltransferase Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Study.
        Am Heart J. 2006; 152: 67-74
        • Meuwese M.C.
        • Duivenvoorden R.
        • Davidson M.D.
        • et al.
        Effect of ACAT inhibition on progression of carotid atherosclerosis in patients with familial hypercholesterolemia, the CAPTIVATE study.
        J Clin Lipidol. 2007; 1: 382
        • von Birgelen B.C.
        • Hartmann M.
        • Mintz G.S.
        • et al.
        Relationship between cardiovascular risk as predicted by established risk scores versus plaque progression as measured by serial intravascular ultrasound in left main coronary arteries.
        Circulation. 2004; 110: 1579-1585
        • Pignoli P.
        • Tremoli E.
        • Poli A.
        • Oreste P.
        • Paoletti R.
        Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging.
        Circulation. 1986; 74: 1399-1406
        • Lorenz M.W.
        • Markus H.S.
        • Bots M.L.
        • Rosvall M.
        • Sitzer M.
        Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis.
        Circulation. 2007; 115: 459-467
        • Byington R.P.
        • Furberg C.D.
        • Crouse III, J.R.
        • Espeland M.A.
        • Bond M.G.
        • Pravastatin
        Lipids, and atherosclerosis in the carotid arteries (PLAC-II).
        Am J Cardiol. 1995; 76: 54C-59C
        • Crouse III, J.R.
        • Byington R.P.
        • Bond M.G.
        • et al.
        Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II).
        Am J Cardiol. 1995; 75: 455-459
        • Hodis H.N.
        • Mack W.J.
        • LaBree L.
        • et al.
        Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial.
        Ann Intern Med. 1996; 124: 548-556
        • MacMahon S.
        • Sharpe N.
        • Gamble G.
        • et al.
        Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group.
        Circulation. 1998; 97: 1784-1790
        • de Groot E.
        • Jukema J.W.
        • Montauban van Swijndregt A.D.
        • et al.
        B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS).
        J Am Coll Cardiol. 1998; 31: 1561-1567
        • Furberg C.D.
        • Adams Jr., H.P.
        • Applegate W.B.
        • et al.
        Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic carotid Artery Progression Study (ACAPS) Research Group.
        Circulation. 1994; 90: 1679-1687
        • Hedblad B.
        • Wikstrand J.
        • Janzon L.
        • Wedel H.
        • Berglund G.
        Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS).
        Circulation. 2001; 103: 1721-1726
        • Mercuri M.
        • Bond M.G.
        • Sirtori C.R.
        • et al.
        Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study.
        Am J Med. 1996; 101: 627-634
        • Salonen R.
        • Nyyssonen K.
        • Porkkala E.
        • et al.
        Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries.
        Circulation. 1995; 92: 1758-1764
        • Crouse III, J.R.
        • Raichlen J.S.
        • Riley W.A.
        • et al.
        Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR trial.
        JAMA. 2007; 297: 1344-1353
        • Duivenvoorden R.
        • Nederveen A.J.
        • de Groot E.
        • Kastelein J.J.
        Atherosclerosis imaging as a benchmark in the development of novel cardiovascular drugs.
        Curr Opin Lipidol. 2007; 18: 613-621
        • Deanfield J.E.
        • Halcox J.P.
        • Rabelink T.J.
        Endothelial function and dysfunction: testing and clinical relevance.
        Circulation. 2007; 115: 1285-1295
        • Corretti M.C.
        • Anderson T.J.
        • Benjamin E.J.
        • et al.
        Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.
        J Am Coll Cardiol. 2002; 39: 257-265
        • Donald A.E.
        • Halcox J.P.
        • Charakida M.
        • et al.
        Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation.
        J Am Coll Cardiol. 2008; 51: 1959-1964
        • Yeboah J.
        • Crouse J.R.
        • Hsu F.C.
        • Burke G.L.
        • Herrington D.M.
        Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study.
        Circulation. 2007; 115: 2390-2397
        • Lieberman E.H.
        • Gerhard M.D.
        • Uehata A.
        • et al.
        Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women.
        Ann Intern Med. 1994; 121: 936-941
        • Muiesan M.L.
        • Salvetti M.
        • Monteduro C.
        • et al.
        Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension.
        Hypertension. 1999; 33: 575-580
        • Treasure C.B.
        • Klein J.L.
        • Weintraub W.S.
        • et al.
        Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.
        N Engl J Med. 1995; 332: 481-487
        • Jodoin I.
        • Bussieres L.M.
        • Tardif J.C.
        • Juneau M.
        Effect of a short-term primary prevention program on endothelium-dependent vasodilation in adults at risk for atherosclerosis.
        Can J Cardiol. 1999; 15: 83-88
        • Raitakari O.T.
        • Ronnemaa T.
        • Jarvisalo M.J.
        • et al.
        Endothelial function in healthy 11-year-old children after dietary intervention with onset in infancy: the Special Turku Coronary Risk Factor Intervention Project for children (STRIP).
        Circulation. 2005; 112: 3786-3794
        • Cai J.
        • Hatsukami T.S.
        • Ferguson M.S.
        • et al.
        In vivo quantitative measurement of intact fibrous cap and lipid-rich necrotic core size in atherosclerotic carotid plaque: comparison of high-resolution, contrast-enhanced magnetic resonance imaging and histology.
        Circulation. 2005; 112: 3437-3444
        • Kerwin W.S.
        • O’Brien K.D.
        • Ferguson M.S.
        • Polissar N.
        • Hatsukami T.S.
        • Yuan C.
        Inflammation in carotid atherosclerotic plaque: a dynamic contrast-enhanced MR imaging study.
        Radiology. 2006; 241: 459-468
        • Crowe L.A.
        • Gatehouse P.
        • Yang G.Z.
        • et al.
        Volume-selective 3D turbo spin echo imaging for vascular wall imaging and distensibility measurement.
        J Magn Reson Imaging. 2003; 17: 572-580
        • Wentzel J.J.
        • Corti R.
        • Fayad Z.A.
        • et al.
        Does shear stress modulate both plaque progression and regression in the thoracic aorta? Human study using serial magnetic resonance imaging.
        J Am Coll Cardiol. 2005; 45: 846-854
        • Yarnykh V.L.
        • Terashima M.
        • Hayes C.E.
        • et al.
        Multicontrast black-blood MRI of carotid arteries: comparison between 1.5 and 3 Tesla magnetic field strengths.
        J Magn Reson Imaging. 2006; 23: 691-698
      2. Duivenvoorden R, de Groot E, Elsen BM, et al. In vivo quantification of carotid artery wall dimensions: 3.0 Tesla MRI versus B-mode ultrasound imaging. Circulation Cardiovascular Imaging; in press.

        • Corti R.
        • Fayad Z.A.
        • Fuster V.
        • et al.
        Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging.
        Circulation. 2001; 104: 249-252
        • Corti R.
        • Fuster V.
        • Fayad Z.A.
        • et al.
        Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging.
        Circulation. 2002; 106: 2884-2887
        • Lima J.A.
        • Desai M.Y.
        • Steen H.
        • Warren W.P.
        • Gautam S.
        • Lai S.
        Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy.
        Circulation. 2004; 110: 2336-2341
        • Yonemura A.
        • Momiyama Y.
        • Fayad Z.A.
        • et al.
        Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques detected by noninvasive magnetic resonance imaging.
        J Am Coll Cardiol. 2005; 45: 733-742
        • Lee J.M.S.
        • Wiesmann F.
        • Shirodaria C.
        • et al.
        Early changes in arterial structure and function following statin initiation: quantification by magnetic resonance imaging.
        Atherosclerosis. 2008; 197: 951-958
        • Zhao X.Q.
        • Yuan C.
        • Hatsukami T.S.
        • et al.
        Effects of prolonged intensive lipid-lowering therapy on the characteristics of carotid atherosclerotic plaques in vivo by MRI: a case–control study.
        Arterioscler Thromb Vasc Biol. 2001; 21: 1623-1629
        • Underhill H.R.
        • Yuan C.
        • Zhao X.Q.
        • et al.
        Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial.
        Am Heart J. 2008; 155: 584-588
        • Jaffer F.A.
        • O’Donnell C.J.
        • Larson M.G.
        • et al.
        Age and sex distribution of subclinical aortic atherosclerosis: a magnetic resonance imaging examination of the Framingham Heart Study.
        Arterioscler Thromb Vasc Biol. 2002; 22: 849-854