Peter Willeit1, Lena Tschiderer1, Michael J Sweeting2, Simon G Thompson3, Matthias W Lorenz4, Elias Allara3, Kathrin Reuber4, Lisa Seekircher1, Lu Gao5, Ximing Liao4, Eva Lonn6, Hertzel C Gerstein7, Salim Yusuf7, Frank P Brouwers8, Folkert W Asselbergs9, Wiek van Gilst10, Sigmund A Anderssen11, Diederick E Grobbee12, John J P Kastelein13, Frank L J Visseren14, George Ntaios15, Apostolos I Hatzitolios16, Christos Savopoulos16, Pythia T Nieuwkerk1, Erik Stroes13, Matthew Walters17, Peter Higgins18, Jesse Dawson18, Paolo Gresele19, Giuseppe Guglielmini19, Rino Migliacci20, Marat Ezhov21, Maya Safarova22, Tatyana Balakhonova23, Eiichi Sato24, Mayuko Amaha24, Tsukasa Nakamura24, Kostas Kapellas25, Lisa M Jamieson25, Michael Skilton26, James A Blumenthal27, Alan Hinderliter28, Andrew Sherwood1, Patrick J Smith27, Michiel A van Agtmael29, Peter Reiss30, Marit G A van Vonderen31, Stefan Kiechl32, Gerhard Klingenschmid1, Matthias Sitzer33, Coen D A Stehouwer34, Heiko Uthoff35, Zhi-Yong Zou36, Ana R Cunha37, Mario F Neves37, Miles D Witham38, Hyun-Woong Park39, Moo-Sik Lee40, Jang-Ho Bae41, Enrique Bernal42, Kristian Wachtell43, Sverre E Kjeldsen43, Michael H Olsen44, David Preiss45, Naveed Sattar46, Edith Beishuizen42, Menno V Huisman47, Mark A Espeland48, Caroline Schmidt49, Stefan Agewall50, Ercan Ok51, Gülay Aşçi51, Eric de Groot52, Muriel P C Grooteman53, Peter J Blankestijn54, Michiel L Bots12. 1. Department of Neurology, Medical University of Innsbruck, Austria (P.W., L.T., L.S., S.K., G.K.). 2. Department of Health Sciences, University of Leicester, United Kingdom (M.J.S.). 3. Department of Public Health and Primary Care, University of Cambridge, United Kingdom (P.W., E.A., M.J.S., S.G.T.). 4. Department of Neurology, Goethe University, Frankfurt am Main, Germany (K.R., X.L., M. Sitzer., M.W.L.). 5. MRC Biostatistics Unit, University of Cambridge, United Kingdom (L.G.). 6. Department of Medicine and Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada (E.L., H.C.G., S.Y.). 7. Hamilton General Hospital, Ontario, Canada (E.L., H.C.G., S.Y.). 8. Department of Cardiology, Haga Teaching Hospital, The Hague, The Netherlands (F.P.B.). 9. Department of Cardiology (F.W.A.), University Medical Center Utrecht, The Netherlands. 10. Department of Experimental Cardiology, University Medical Center Groningen, The Netherlands (W.v.G.). 11. Department of Sports Medicine, Norwegian School of Sports Sciences, Oslo, Norway (S.A.A.). 12. Julius Center for Health Sciences and Primary Care (D.E.G., M.L.B.), University Medical Center Utrecht, The Netherlands. 13. Department of Vascular Medicine (J.J.P.K., E.S.), Academic Medical Centre, University of Amsterdam, The Netherlands. 14. Department of Vascular Medicine (F.L.J.V.), University Medical Center Utrecht, The Netherlands. 15. Department of Medicine, University of Thessaly, Larissa, Greece (G.N.). 16. 1st Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Greece (A.I.H., C.S.). 17. School of Medicine, Dentistry and Nursing (M.W.), University of Glasgow, United Kingdom. 18. Institute of Cardiovascular and Medical Sciences (P.H., J.D.), University of Glasgow, United Kingdom. 19. Division of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Italy (P.G., G.G.). 20. Division of Internal Medicine, Cortona Hospital, Italy (R.M.). 21. Laboratory of Lipid Disorders, National Medical Research Center of Cardiology, Moscow, Russia (M.E.), National Medical Research Center of Cardiology, Moscow, Russia. 22. Atherosclerosis Department (M. Safarova), National Medical Research Center of Cardiology, Moscow, Russia. 23. Ultrasound Vascular Laboratory (T.B.), National Medical Research Center of Cardiology, Moscow, Russia. 24. Division of Nephrology, Shinmatsudo Central General Hospital, Chiba, Japan (E.S., M.A., T.N.). 25. Australian Research Centre for Population Oral Health, University of Adelaide, SA, Australia (K.K., L.M.J.). 26. Boden Institute of Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney, NSW, Australia (M.Skilton). 27. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, (J.A.B., A.S., P.J.S.). 28. Department of Medicine, University of North Carolina, Chapel Hill (A.H.). 29. Department of Internal Medicine (M.A.v.A.) Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands. 30. Amsterdam Institute for Global Health and Development, University of Amsterdam, The Netherlands (P.R.). 31. Department of Internal Medicine, Medical Center Leeuwarden, The Netherlands (M.G.A.v.V.). 32. VASCage GmbH, Research Centre on Vascular Ageing and Stroke, Innsbruck, Austria (S.K.). 33. Department of Neurology, Klinikum Herford, Herford, Germany (M. Sitzer). 34. Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, The Netherlands (C.D.A.S.). 35. Department of Angiology, University Hospital Basel, Switzerland (H.U.). 36. Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China (Z.-Y.Z.). 37. Department of Clinical Medicine, State University of Rio de Janeiro, Brazil (A.R.C., M.F.N.). 38. AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle-upon-Tyne Hospitals Trust, United Kingdom (M.D.W.). 39. Department of Internal Medicine, Gyeongsang National University Hospital, Daejeon, South Korea (H.-W.P., M.-S.L.). 40. Department of Preventive Medicine, Konyang University, Jinju, South Korea (M.-S.L.). 41. Heart Center, Konyang University Hospital, Daejeon, South Korea (J.-H.B.). 42. Infectious Diseases Unit, Reina Sofia Hospital, Murcia, Spain (E.B.). 43. Department of Cardiology, Oslo University Hospital, Norway (K.W., S.E.K.). 44. Department of Internal Medicine, Holbaek Hospital, University of Southern Denmark, Odense (M.H.O.). 45. MRC Population Health Research Unit, Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (D.P.). 46. BHF Glasgow Cardiovascular Research Centre (N.S.), University of Glasgow, United Kingdom. 47. Department of Thrombosis and Hemostasis, Leiden University Medical Center, The Netherlands (M.V.H.). 48. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC (M.A.E.). 49. Wallenberg Laboratory for Cardiovascular Research, University of Gothenburg, Sweden (C.S.). 50. Oslo University Hospital Ullevål and Institute of Clinical Sciences, University of Oslo, Norway (S.A.). 51. Nephrology Department, Ege University School of Medicine, Bornova-Izmir, Turkey (E.O, G.A.). 52. Imagelabonline & Cardiovascular, Eindhoven and Lunteren, the Netherlands (E.d.G.). 53. Department of Nephrology (M.P.C.G.), Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands. 54. Department of Nephrology (P.J.B.), University Medical Center Utrecht, The Netherlands.
Abstract
BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.
BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.
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