Traditional and new composite endpoints in heart failure clinical trials: Facilitating comprehensive efficacy assessments and improving trial efficiency

European Journal of Heart Failure

Volumn 18, Issue 5, 2016, Pages 482-489

  Anker, Stefan D ^a   Schroeder, Stefan ^b   Atar, Dan ^c   Bax, Jeroen J ^d   Ceconi, Claudio ^e   Cowie, Martin R ^f   Crisp, Adam ^g   Dominjon, Fabienne ^h   Ford, Ian ⁱ   Ghofrani, Hossein Ardeschir ^j,k,l   Gropper, Savion ^m   Hindricks, Gerhard ⁿ   Hlatky, Mark A ^o   Holcomb, Richard ^p   Honarpour, Narimon ^q   Jukema, J Wouter ^d   Kim, Albert M ^r   Kunz, Michael ^b   Lefkowitz, Martin ^s   Le Floch, Chantal ^h   Landmesser, Ulf ^t   McDonagh, Theresa A ^u   McMurray, John J ^v   Merkely, Bela ^w   Packer, Milton ^x   Prasad, Krishna ^y   Revkin, James ^r   Rosano, Giuseppe M C ^z,aa   Somaratne, Ransi ^q   Stough, Wendy Gattis ^ab   Voors, Adriaan A ^ac   Ruschitzka, Frank ^ad   more..

^a UNIVERSITY MEDICAL CENTER GÖTTINGEN   (Germany)

^b BAYER PHARMA AG   (Germany)

^c ULLEVÅL UNIVERSITY HOSPITAL   (Norway)

^d LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^e Hospital of Desenzano del Garda   (Italy)

^f NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^g GLAXOSMITHKLINE   (United Kingdom)

^h INSTITUT DE RECHERCHES INTERNATIONALES SERVIER   (France)

ⁱ UNIVERSITY OF GLASGOW   (United Kingdom)

^j JUSTUS LIEBIG UNIVERSITY   (Germany)

^k KERCKHOFF HEART CENTER   (Germany)

^l IMPERIAL COLLEGE LONDON   (United Kingdom)

^m BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

ⁿ UNIVERSITY OF LEIPZIG   (Germany)

^o STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^p Independent Biostatistician   (United States)

^q AMGEN INC   (United States)

^r PFIZER INC   (United States)

^s NOVARTIS PHARMA AG   (Switzerland)

^t CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^u KING S COLLEGE HOSPITAL   (United Kingdom)

^v UNIVERSITY OF GLASGOW   (United Kingdom)

^w SEMMELWEIS UNIVERSITY   (Hungary)

^x UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^y MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY   (United Kingdom)

^z IRCCS SAN RAFFAELE PISANA   (Italy)

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

^ab CAMPBELL UNIVERSITY   (United States)

^ac UNIVERSITY OF GRONINGEN   (Netherlands)

^ad UNIVERSITY HOSPITAL ZURICH   (Switzerland)

more..

Author keywords

Clinical trial; Endpoint determination; Heart failure; Surrogate endpoints

Indexed keywords

CANDESARTAN; IVABRADINE; PLACEBO; VALSARTAN;

CARDIOVASCULAR MORTALITY; CLINICAL TRIAL (TOPIC); DRUG APPROVAL; DRUG SAFETY; EXERCISE TOLERANCE; FUNCTIONAL STATUS; HEART ARREST; HEART FAILURE; HOSPITAL ADMISSION; HOSPITAL READMISSION; HOSPITALIZATION; HUMAN; MORTALITY; OUTCOME ASSESSMENT; PRIORITY JOURNAL; QUALITY OF LIFE; RECURRENT EVENT ANALYSIS; RESPONDER ANALYSIS; REVIEW; RISK REDUCTION; STATISTICAL ANALYSIS; SYSTOLIC HEART FAILURE; CAUSE OF DEATH; DAILY LIFE ACTIVITY; TREATMENT OUTCOME;

ACTIVITIES OF DAILY LIVING; CAUSE OF DEATH; CLINICAL TRIALS AS TOPIC; HEART FAILURE; HOSPITALIZATION; HUMANS; MORTALITY; OUTCOME ASSESSMENT (HEALTH CARE); QUALITY OF LIFE; TREATMENT OUTCOME;

EID: 84963679505     PISSN: 13889842     EISSN: 18790844     Source Type: Journal    
DOI: 10.1002/ejhf.516     Document Type: Review

References (62)

1. Zannad F, Garcia AA, Anker SD, Armstrong PW, Calvo G, Cleland JG, Cohn JN, Dickstein K, Domanski MJ, Ekman I, Filippatos GS, Gheorghiade M, Hernandez AF, Jaarsma T, Koglin J, Konstam M, Kupfer S, Maggioni AP, Mebazaa A, Metra M, Nowack C, Pieske B, Pina IL, Pocock SJ, Ponikowski P, Rosano G, Ruilope LM, Ruschitzka F, Severin T, Solomon S, Stein K, Stockbridge NL, Stough WG, Swedberg K, Tavazzi L, Voors AA, Wasserman SM, Woehrle H, Zalewski A, McMurray JJ,. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail 2013; 15: 1082-1094.
2. Cordoba G, Schwartz L, Woloshin S, Bae H, Gotzsche PC,. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ 2010; 341: c3920.
3. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C,. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA 2003; 289: 2554-2559.
4. European Network for Health Technology Assessment. Endpoints used for relative effectiveness assessment of pharmaceuticals: clinical endpoints. https://eunethta.fedimbo.belgium.be/sites/5026.fedimbo.belgium.be/files/Clinical%20endpoints.pdf (15 February 2015).
5. Jackson N, Atar D, Borentain M, Breithardt G, van Eickels M, Endres M, Fraass U, Friede T, Hannachi H, Janmohamed S, Kreuzer J, Landray M, Lautsch D, Le Floch C, Mol P, Naci H, Samani N, Svensson A, Thorstensen C, Tijssen J, Vandzhura V, Zalewski A, Kirchhof P,. Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology. Eur Heart J 2016; 37: 747-754.
6. Roe MT, Mahaffey KW, Ezekowitz JA, Alexander JH, Goodman SG, Hernandez A, Temple T, Berdan L, Califf RM, Harrington RA, Peterson ED, Armstrong PW,. The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations. Am Heart J 2015; 169: 743-750.
7. Moses H III, Matheson DH, Cairns-Smith S, George BP, Palisch C, Dorsey ER,. The anatomy of medical research: US and international comparisons. JAMA 2015; 313: 174-189.
8. Gomez G, Gomez-Mateu M, Dafni U,. Informed choice of composite end points in cardiovascular trials. Circ Cardiovasc Qual Outcomes 2014; 7: 170-178.
9. Pogue J, Thabane L, Devereaux PJ, Yusuf S,. Testing for heterogeneity among the components of a binary composite outcome in a clinical trial. BMC Med Res Methodol 2010; 10: 49.
10. Pogue J, Devereaux PJ, Thabane L, Yusuf S,. Designing and analyzing clinical trials with composite outcomes: consideration of possible treatment differences between the individual outcomes. PLoS One 2012; 7:e34785.
11. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S, CHARM Investigators, and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759-766.
12. Wolbers M, Koller MT, Stel VS, Schaer B, Jager KJ, Leffondre K, Heinze G,. Competing risks analyses: objectives and approaches. Eur Heart J 2014; 35: 2936-2941.
13. Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA, Bryant DM, onso-Coello P, Alonso J, Worster A, Upadhye S, Jaeschke R, Schunemann HJ, Permanyer-Miralda G, Pacheco-Huergo V, Domingo-Salvany A, Wu P, Mills EJ, Guyatt GH,. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ 2007; 334: 786.
14. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L,. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376: 875-885.
15. Bohm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L,. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol 2013; 102: 11-22.
16. Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators,. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667-1675.
17. Armstrong PW, Westerhout CM, Van de Werf F, Califf RM, Welsh RC, Wilcox RG, Bakal JA,. Refining clinical trial composite outcomes: an application to the Assessment of the Safety and Efficacy of a New Thrombolytic-3 (ASSENT-3) trial. Am Heart J 2011; 161: 848-854.
18. Buyse M., Generalized pairwise comparisons of prioritized outcomes in the two-sample problem. Stat Med 2010; 29: 3245-3257.
19. Pocock SJ, Ariti CA, Collier TJ, Wang D,. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. Eur Heart J 2012; 33: 176-182.
20. Rauch G, Jahn-Eimermacher A, Brannath W, Kieser M,. Opportunities and challenges of combined effect measures based on prioritized outcomes. Stat Med 2014; 33: 1104-1120.
21. Rauch G, Rauch B, Schuler S, Kieser M,. Opportunities and challenges of clinical trials in cardiology using composite primary endpoints. World J Cardiol 2015; 7: 1-5.
22. Subherwal S, Anstrom KJ, Jones WS, Felker MG, Misra S, Conte MS, Hiatt WR, Patel MR,. Use of alternative methodologies for evaluation of composite end points in trials of therapies for critical limb ischemia. Am Heart J 2012; 164: 277-284.
23. Cleland JG,. How to assess new treatments for the management of heart failure: composite scoring systems to assess the patients' clinical journey. Eur J Heart Fail 2002; 4: 243-247.
24. Dev S, Clare RM, Felker GM, Fiuzat M, Warner SL, O'Connor CM,. Link between decisions regarding resuscitation and preferences for quality over length of life with heart failure. Eur J Heart Fail 2012; 14: 45-53.
25. Stevenson LW, Hellkamp AS, Leier CV, Sopko G, Koelling T, Warnica JW, Abraham WT, Kasper EK, Rogers JG, Califf RM, Schramm EE, O'Connor CM,. Changing preferences for survival after hospitalization with advanced heart failure. J Am Coll Cardiol 2008; 52: 1702-1708.
26. Packer M., Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail 2001; 7: 176-182.
27. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E,. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 2013; 309: 1268-1277.
28. Abraham WT, Young JB, Leon AR, Adler S, Bank AJ, Hall SA, Lieberman R, Liem LB, O'Connell JB, Schroeder JS, Wheelan KR,. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation 2004; 110: 2864-2868.
29. Packer M, Colucci W, Fisher L, Massie BM, Teerlink JR, Young J, Padley RJ, Thakkar R, Delgado-Herrera L, Salon J, Garratt C, Huang B, Sarapohja T,. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 2013; 1: 103-111.
30. Hindricks G, Taborsky M, Glikson M, Heinrich U, Schumacher B, Katz A, Brachmann J, Lewalter T, Goette A, Block M, Kautzner J, Sack S, Husser D, Piorkowski C, Sogaard P,. Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial. Lancet 2014; 384: 583-590.
31. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de FS, Despres J, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB,. Heart Disease and Stroke Statistics-2015 update: a report from the American Heart Association. Circulation 2015; 131: e29-e322.
32. Packer M, Narahara KA, Elkayam U, Sullivan JM, Pearle DL, Massie BM, Creager MA,. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. J Am Coll Cardiol 1993; 22: 65-72.
33. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G,. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30: 2493-2537.
34. Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, Palevsky HI, Rich S, Sood N, Rosenzweig EB, Trow TK, Yung R, Elliott CG, Badesch DB,. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest 2014; 146: 449-475.
35. Anker SD, Agewall S, Borggrefe M, Calvert M, Jaime CJ, Cowie MR, Ford I, Paty JA, Riley JP, Swedberg K, Tavazzi L, Wiklund I, Kirchhof P,. The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials. Eur Heart J 2014; 35: 2001-2009.
36. Food and Drug Administration. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Guidance for Industry 2009.
37. European Medicines Agency. Innovative drug development approaches: final report from the EMEA/CHMP think-tank group on innovative drug development. http://www.ema.europa.eu/docs/en-GB/document-library/Other/2009/10/WC500004913.pdf (30 April 2015).
38. European Medicines Agency. Pilot project on adaptive licensing. http://www.ema.europa.eu/docs/en-GB/document-library/Other/2014/03/WC500163409.pdf (26 June 2014).
39. Eichler HG, Oye K, Baird LG, Abadie E, Brown J, Drum CL, Ferguson J, Garner S, Honig P, Hukkelhoven M, Lim JC, Lim R, Lumpkin MM, Neil G, O'Rourke B, Pezalla E, Shoda D, Seyfert-Margolis V, Sigal EV, Sobotka J, Tan D, Unger TF, Hirsch G,. Adaptive licensing: taking the next step in the evolution of drug approval. Clin Pharmacol Ther 2012; 91: 426-437.
40. European Medicines Agency. Guideline on good pharmacovigilance practices (GVP): Module VIII Post authorisation safety studies (Rev 1). http://www.ema.europa.eu/docs/en-GB/document-library/Scientific-guideline/2012/06/WC500129137.pdf (30 March 2015).
41. Rosano GMC, Anker S, Marrocco W, Coats AJS,. Adaptive licensing: a way forward in the approval process of new therapeutic agents in Europe. Clin Trials Regul Sci Cardiol 2015; 1: 1-2.
42. Anker SD, McMurray JJ,. Time to move on from 'time-to-first': should all events be included in the analysis of clinical trials? Eur Heart J 2012; 33: 2764-2765.
43. Dunlay SM, Shah ND, Shi Q, Morlan B, VanHouten H, Long KH, Roger VL,. Lifetime costs of medical care after heart failure diagnosis. Circ Cardiovasc Qual Outcomes 2011; 4: 68-75.
44. Bradley EH, Curry LA, Krumholz HM,. Strategies to reduce heart failure readmissions. JAMA 2014; 311: 1160.
45. Joynt KE, Jha AK,. A path forward on Medicare readmissions. N Engl J Med 2013; 368: 1175-1177.
46. Rogers JK, McMurray JJ, Pocock SJ, Zannad F, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pitt B,. Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations. Circulation 2012; 126: 2317-2323.
47. Borer JS, Bohm M, Ford I, Komajda M, Tavazzi L, Sendon JL, Alings M, Lopez-de-Sa E, Swedberg K,. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J 2012; 33: 2813-2820.
48. Rogers JK, Pocock SJ, McMurray JJ, Granger CB, Michelson EL, Ostergren J, Pfeffer MA, Solomon SD, Swedberg K, Yusuf S,. Analysing recurrent hospitalizations in heart failure: a review of statistical methodology, with application to CHARM-Preserved. Eur J Heart Fail 2014; 16: 33-40.
49. Rogers JK, Jhund PS, Perez AC, Bohm M, Cleland JG, Gullestad L, Kjekshus J, van Veldhuisen DJ, Wikstrand J, Wedel H, McMurray JJ, Pocock SJ,. Effect of rosuvastatin on repeat heart failure hospitalizations: the CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure). JACC Heart Fail 2014; 2: 289-297.
50. Amorim LD, Cai J,. Modelling recurrent events: a tutorial for analysis in epidemiology. Int J Epidemiol 2015; 44: 324-333.
51. Abraham WT, Adamson PB, Bourge RC, Aaron MF, Costanzo MR, Stevenson LW, Strickland W, Neelagaru S, Raval N, Krueger S, Weiner S, Shavelle D, Jeffries B, Yadav JS,. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet 2011; 377: 658-666.
52. Rogers, J., Recurrent events analysis, not so straightforward! http://www.statisticsviews.com/details/feature/5786631/Recurrent-events-analysis-not-so-straightforward.html (28 January 2014).
53. Novartis Pharmaceuticals,. Efficacy and safety of LCZ696 compared to valsartan on morbidity and mortality in heart failure patients with preserved ejection fraction (PARAGON-HF). https://clinicaltrials.gov/ct2/show/NCT01920711 (30 May 2015).
54. Committee for Medicinal Products for Human Use (CHMP). Guideline on the choice of the non-inferiority margin. EMEA/CPMP/EWP/21 58/99 2005. http://www.ema.europa.eu/docs/en-GB/document-library/Scientific-guideline/2009/09/WC500003417.pdf
55. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Guideline on missing data in confirmatory clinical trials (EMA/CPMP/EWP/1776/99). http://wwwemaeuropaeu/docs/en-GB/document-library/Scientific-guideline/2010/09/WC500096793pdf 2010.
56. Senn S., Disappointing dichotomies. Pharmaceut Stat 2003; 2: 239-240.
57. Lewis JA,. In defence of the dichotomy. Pharmaceut Stat 2004; 3: 77-79.
58. Hawkins NM, Petrie MC, Burgess MI, McMurray JJ,. Selecting patients for cardiac resynchronization therapy: the fallacy of echocardiographic dyssynchrony. J Am Coll Cardiol 2009; 53: 1944-1959.
59. Snapinn SM, Jiang Q,. Responder analyses and the assessment of a clinically relevant treatment effect. Trials 2007; 8: 31.
60. Vaduganathan M, Greene SJ, Ambrosy AP, Gheorghiade M, Butler J,. The disconnect between phase II and phase III trials of drugs for heart failure. Nat Rev Cardiol 2013; 10: 85-97.
61. Hayward RA, Kent DM, Vijan S, Hofer TP,. Multivariable risk prediction can greatly enhance the statistical power of clinical trial subgroup analysis. BMC Med Res Methodol 2006; 6: 18.
62. Kent DM, Rothwell PM, Ioannidis JP, Altman DG, Hayward RA,. Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials 2010; 11: 85.