Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints

Author:

Rossignol Patrick12,Agarwal Rajiv34,Canaud Bernard5,Charney Alan6,Chatellier Gilles7,Craig Jonathan C89,Cushman William C10,Gansevoort Ronald T11,Fellström Bengt12,Garza Dahlia13,Guzman Nicolas14,Holtkamp Frank A1516,London Gerard M217,Massy Ziad A218,Mebazaa Alexandre2192021,Mol Peter G M1516,Pfeffer Marc A22,Rosenberg Yves23,Ruilope Luis M24,Seltzer Jonathan25,Shah Amil M22,Shah Salim26,Singh Bhupinder27,Stefánsson Bergur V28,Stockbridge Norman29,Stough Wendy Gattis30,Thygesen Kristian31,Walsh Michael32,Wanner Christoph33,Warnock David G34,Wilcox Christopher S35,Wittes Janet36,Pitt Bertram37,Thompson Aliza29,Zannad Faiez12

Affiliation:

1. Inserm, Centre d’Investigations Cliniques- 1433, and Inserm U1116; CHRU Nancy; Université de Lorraine; Association Lorraine pour le Traitement de l’Insuffisance Rénale, Institut lorrain du Cœur et des Vaisseaux Louis Mathieu, 4 rue du Morvan, Nancy, France

2. F-CRIN INI-CRCT, Nancy, France

3. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

4. Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA

5. Fresenius Medical Care Deutschland and University of Montpellier, UFR Medicine, France

6. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

7. AP-HP, Hôpital Européen Georges Pompidou, Unité de Recherche Clinique and INSERM CIC 1418, Paris, France

8. School of Public Health, The University of Sydney, New South Wales, Australia

9. Centre for Kidney Research, The Children's Hospital at Westmead, New South Wales, Australia

10. Preventive Medicine Section, Veterans Affairs Medical Center, Memphis, Tennessee, USA

11. Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

12. Inserm U1018, Université Paris-Saclay, UVSQ, Université. Paris-Sud, Villejuif, France

13. Relypsa, Inc., Redwood City, CA, USA

14. AstraZeneca, Gaithersburg, MD, USA

15. Dutch Medicines Evaluation Board, Utrecht, The Netherlands

16. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

17. France Centre Hospitalier F.H. Manhès, Fleury-Merogis, France

18. Ambroise Pare University Hospital, APHP, Paris-Ile-de France-Ouest University (UVSQ), and INSERM U1018, Team 5 Boulogne Billancourt, France

19. U942 Inserm, Paris, France

20. University Paris Diderot, Sorbonne Paris Cité, Paris, France

21. APHP, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint Louis-Lariboisière, Paris, France

22. Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

23. National Heart, Lung, and Blood Institute, Bethesda, MD, USA

24. Institute of Investigation and Hypertension Unit, Hospital 12 de Octubre, Department of Preventive Medicine and Public Health, Universidad Autonoma and School of Doctoral Studies and Research, Universidad Europea de Madrid, Madrid, Spain

25. ACI Clinical, Bala Cynwyd, PA, USA

26. Sarfez Pharmaceuticals, Inc., McLean, VA, USA

27. ZS Pharma, San Mateo, CA, USA

28. AstraZeneca, Gothenburg, Sweden

29. Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

30. Campbell University College of Pharmacy and Health Sciences, NC, USA

31. Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

32. McMaster University and Population Health Research Institute, Hamilton, Canada

33. Division of Nephrology, Department of Internal Medicine 1, University Hospital Würzburg and Comprehensive Heart Failure Center, Würzburg, Germany

34. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

35. Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine, Georgetown University, Washington, DC, USA

36. Statistics Collaborative, Inc., Washington, District of Columbia, USA

37. University of Michigan School of Medicine, Ann Arbor, MI, USA

Abstract

Abstract Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.

Funder

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine

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