Skip to main content

Advertisement

SpringerLink
Log in

Site selection for heart failure clinical trials in the USA

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

ABSTRACT

There are more than 1 million primary hospitalizations for heart failure (HF) annually in the USA alone, and post-discharge outcomes remain persistently poor despite available therapies and quality improvement initiatives. Recent international randomized clinical trials in hospitalized HF have repeatedly failed to improve this post-discharge event rate. A potential reason for this persistent lack of clinical trial success that has not previously received significant attention relates to site selection and the generally low level of patient enrollment from the USA. Only ~5 % of US hospitals participate in clinical trials, and in four recent randomized trials of hospitalized HF, only one-third of patients were enrolled in North America. This poor participation among US centers has necessitated disproportionate enrollment from non-US sites. Regional variations in HF patient characteristics and clinical outcomes are well documented, and a lack of US patient representation in clinical trials limits the generalizability of results and presents obstacles for US regulatory agency approval. There are multiple impediments to successful US enrollment including a lack of incentive for investigators and institutions, the relative value unit-based compensation system, poor institutional framework for identification of appropriate patients, and increasing liability to conduct trials. In this manuscript, we specifically identify barriers to successful hospitalized HF clinical trial participation in the USA and suggest possible solutions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Roger VL, Go AS, Lloyd-Jones DM et al (2012) Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation 125:e2–e220

    Article  PubMed Central  PubMed  Google Scholar 

  2. Gheorghiade M, Abraham WT, Albert NM et al (2006) Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 296:2217–2226

    Article  CAS  PubMed  Google Scholar 

  3. Konstam MA, Gheorghiade M, Burnett JC Jr et al (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA 297:1319–1331

    Article  CAS  PubMed  Google Scholar 

  4. Massie BM, O’Connor CM, Metra M et al (2010) Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 363:1419–1428

    Article  PubMed  Google Scholar 

  5. O’Connor CM, Starling RC, Hernandez AF et al (2011) Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 365:32–43

    Article  PubMed  Google Scholar 

  6. Felker GM, Pang PS, Adams KF et al (2010) Clinical trials of pharmacological therapies in acute heart failure syndromes: lessons learned and directions forward. Circ Heart Fail 3:314–325

    Article  PubMed  Google Scholar 

  7. Gheorghiade M, Adams KF, Cleland JG et al (2009) Phase III clinical trial end points in acute heart failure syndromes: a virtual roundtable with the Acute Heart Failure Syndromes International Working Group. Am Heart J 157:957–970

    Article  PubMed  Google Scholar 

  8. Gheorghiade M, Pang PS, O’Connor CM et al (2011) Clinical development of pharmacologic agents for acute heart failure syndromes: a proposal for a mechanistic translational phase. Am Heart J 161:224–232

    Article  CAS  PubMed  Google Scholar 

  9. Gheorghiade M, Zannad F, Sopko G et al (2005) Acute heart failure syndromes: current state and framework for future research. Circulation 112:3958–3968

    Article  PubMed  Google Scholar 

  10. Califf RM, Harrington RA (2011) American industry and the U.S. Cardiovascular Clinical Research Enterprise an appropriate analogy? J Am Coll Cardiol 58:677–680

    Article  PubMed  Google Scholar 

  11. Eapen ZJ, Vavalle JP, Granger CB, Harrington RA, Peterson ED, Califf RM (2013) Rescuing clinical trials in the United States and beyond: a call for action. Am Heart J 165:837–847

    Article  PubMed  Google Scholar 

  12. Velazquez EJ, Lee KL, Deja MA et al (2011) Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 364:1607–1616

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Blair JE, Zannad F, Konstam MA et al (2008) Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (efficacy of vasopressin antagonism in heart failure: outcome study with tolvaptan) program. J Am Coll Cardiol 52:1640–1648

    Article  PubMed  Google Scholar 

  14. O’Connor CM, Fiuzat M, Swedberg K et al (2011) Influence of global region on outcomes in heart failure beta-blocker trials. J Am Coll Cardiol 58:915–922

    Article  PubMed  Google Scholar 

  15. MacMahon S, Perkovic V, Patel A (2013) Industry-sponsored clinical trials in emerging markets: time to review the terms of engagement. JAMA 310:907–908

    Article  CAS  PubMed  Google Scholar 

  16. Glickman SW, McHutchison JG, Peterson ED et al (2009) Ethical and scientific implications of the globalization of clinical research. N Engl J Med 360:816–823

    Article  CAS  PubMed  Google Scholar 

  17. Butler J, Fonarow GC, O’Connor C et al (2015) Improving cardiovascular clinical trials in the United States: recommendation from clinicians, researchers, sponsors, and regulators. Am Heart J [in press]

  18. Gheorghiade M, Bohm M, Greene SJ et al (2013) Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial. JAMA 309:1125–1135

    Article  CAS  PubMed  Google Scholar 

  19. Pitt B, Pfeffer MA, Assmann SF et al (2014) Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 370:1383–1392

    Article  CAS  PubMed  Google Scholar 

  20. Shah AM, Shah SJ, Anand IS et al (2014) Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail 7:104–115

    Article  CAS  PubMed  Google Scholar 

  21. Teerlink JR, Cotter G, Davison BA et al (2013) Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 381:29–39

    Article  CAS  PubMed  Google Scholar 

  22. McMurray JJ, Packer M, Desai AS et al (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004

    Article  PubMed  Google Scholar 

  23. Massie BM, Carson PE, McMurray JJ et al (2008) Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 359:2456–2467

    Article  CAS  PubMed  Google Scholar 

  24. Butler J, Subacius H, Vaduganathan M et al (2013) Relationship between clinical trial site enrollment with participant characteristics, protocol completion, and outcomes: insights from the EVEREST (efficacy of vasopressin antagonism in heart failure: outcome study with tolvaptan) trial. J Am Coll Cardiol 61:571–579

    Article  PubMed  Google Scholar 

  25. Summer R, Wiener RS, Carroll D, Sager A (2012) Physician perception of the impact of productivity measures on academic practice. Arch Intern Med 172:967–969

    Article  PubMed Central  PubMed  Google Scholar 

  26. Mezrich R, Nagy PG (2007) The academic RVU: a system for measuring academic productivity. J Am Coll Radiol 4:471–478

    Article  PubMed  Google Scholar 

  27. Gheorghiade M, Vaduganathan M, Greene SJ et al (2014) Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions. Heart Fail Rev 19:135–152

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Dickert NW, Llanos A, Samady H (2012) Re-visiting consent for clinical research on acute myocardial infarction and other emergent conditions. Prog Cardiovasc Dis 55:251–257

    Article  PubMed  Google Scholar 

  29. Shahzad A, Kemp I, Mars C et al (2014) Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 384:1849–1858

    Article  CAS  PubMed  Google Scholar 

  30. Harinstein ME, Flaherty JD, Fonarow GC et al (2011) Clinical assessment of acute heart failure syndromes: emergency department through the early post-discharge period. Heart 97:1607–1618

    Article  PubMed  Google Scholar 

  31. Adams KF Jr, Fonarow GC, Emerman CL et al (2005) Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 149:209–216

    Article  PubMed  Google Scholar 

  32. Cleland JG, Swedberg K, Follath F et al (2003) The EuroHeart Failure survey programme—a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 24:442–463

    Article  CAS  PubMed  Google Scholar 

  33. Gheorghiade M, Pang PS (2009) Acute heart failure syndromes. J Am Coll Cardiol 53:557–573

    Article  PubMed  Google Scholar 

  34. Getz KA, Wenger J, Campo RA, Seguine ES, Kaitin KI (2008) Assessing the impact of protocol design changes on clinical trial performance. Am J Ther 15:450–457

    Article  PubMed  Google Scholar 

  35. Oliva F, Mortara A, Cacciatore G et al (2012) Acute heart failure patient profiles, management and in-hospital outcome: results of the Italian Registry on Heart Failure Outcome. Eur J Heart Fail 14:1208–1217

    Article  PubMed  Google Scholar 

  36. Markman M, Smoyer L, Marron JT, Montgomery R (2007) Cancer versus heart failure patient self-declared potential interest in clinical trials. Curr Oncol Rep 9:1–5

    Article  PubMed  Google Scholar 

  37. Greene SJ, Shah AN, Butler J et al (2014) Designing effective drug and device development programs for hospitalized heart failure: a proposal for pretrial registries. Am Heart J 168:142–149

    Article  PubMed  Google Scholar 

  38. Hess CN, Rao SV, Kong DF et al (2013) Embedding a randomized clinical trial into an ongoing registry infrastructure: unique opportunities for efficiency in design of the study of access site for enhancement of percutaneous coronary intervention for women (SAFE-PCI for women). Am Heart J 166(421–428):e1

    Google Scholar 

  39. Frobert O, Lagerqvist B, Olivecrona GK et al (2013) Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med 369:1587–1597

    Article  CAS  PubMed  Google Scholar 

  40. Svilaas T, Vlaar PJ, van der Horst IC et al (2008) Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med 358:557–567

    Article  CAS  PubMed  Google Scholar 

  41. Lauer MS, D’Agostino RB Sr (2013) The randomized registry trial—the next disruptive technology in clinical research? N Engl J Med 369:1579–1581

    Article  CAS  PubMed  Google Scholar 

  42. Eapen ZJ, Lauer MS, Temple RJ (2014) The imperative of overcoming barriers to the conduct of large, simple trials. JAMA 311:1397–1398

    Article  CAS  PubMed  Google Scholar 

  43. Reiter KL, Song PH, Minasian L, Good M, Weiner BJ, McAlearney AS (2012) A method for analyzing the business case for provider participation in the National Cancer Institute’s Community Clinical Oncology Program and similar federally funded, provider-based research networks. Cancer 118:4253–4261

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The opinions and information in this article are those of the authors and do not represent the views and/or policies of the US Food and Drug Administration.

Conflict of interest

JB.: Research support: National Institutes of Health, European Union, Health Resource Services Administration, Food and Drug Administration, Consultant: Amgen, Bayer, Celladon, Gambro, GE Healthcare, Janssen, Medtronic, Novartis, Ono, Relypsa, Trevena, Stock options: Stemedica; G. C. F.: Research AHRQ significant, NHLBI significant, Consultant: Novartis significant, Medtronic modest, Bayer modest, Gambro modest, Janssen modest; C. M. O.: none; M.A.P.: Research Support: Amgen, Celladon, Novartis, Sanofi-Aventis, Consultant: Aastrom, Abbott Vascular, Amgen, Cerenis, Concert, Fibrogen, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Roche, Servier, Teva, University of Oxford; M. R. M.: Consultant: Boston Scientific, St. Jude’s, Medtronic, Johnson and Johnson, ABIM, NIH/NHLBI, Baxter, Abbott Vascular, Thoratec; R. J. M. receives research support from Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, Otsuka, and ResMed; honoraria from Thoratec; and has served on an advisory board for Luitpold Pharmaceuticals, Inc; S. P. C.: Research support: NIH/NHLBI, Medtronic, Cardiorentis, Abbott Point-of-Care, Novartis, The Medicines Company, Astellas, Consultant: Trevena, Novartis, Otsuka, Radiometer, The Medicines Company, Medtronic, BRAHMS, Insys; J. J. V. M.: none; W. D. is a full time employee of Bayer Pharma; F. M. is a full time employee of Bayer Pharma; M. G.: Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S. A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson and Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT,Takeda Pharmaceuticals North America, Inc and Trevena Therapeutics; and has received significant (>$10,000) support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic, Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT and Takeda Pharmaceuticals North America, Inc. All others authors report no conflicts of interest.

Author information

Authors and Affiliations

  1. Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Matthew E. Harinstein

  2. Division of Cardiology, Stony Brook University School of Medicine, Stony Brook, NY, USA

    Javed Butler

  3. Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, 201 East Huron Street, Galter 3-150, Chicago, IL, USA

    Stephen J. Greene, Robert O. Bonow & Mihai Gheorghiade

  4. Ahmanson-UCLA Cardiomyopathy Center, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA

    Gregg C. Fonarow

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

    Norman L. Stockbridge

  6. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA

    Christopher M. O’Connor, Mona Fiuzat & Robert J. Mentz

  7. Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston, MA, USA

    Marc A. Pfeffer, Mandeep R. Mehra & Scott D. Solomon

  8. Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Clyde W. Yancy

  9. Department of Emergency Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    Sean P. Collins

  10. Institute of Cardiovascular and Medical Sciences, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

    John J. V. McMurray

  11. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Muthiah Vaduganathan

  12. Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Preston M. Dunnmon

  13. Division of Cardiology, IRCC San Raffaele, Rome, Italy

    Giuseppe M. C. Rosano

  14. Global Drug Discovery, Clinical Sciences, Experimental Medicine, Bayer Pharma AG, Berlin, Germany

    Wilfried Dinh & Frank Misselwitz

  15. Department of Cardiology, Witten University, Witten, Germany

    Wilfried Dinh

Authors
  1. Matthew E. Harinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javed Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen J. Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregg C. Fonarow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Norman L. Stockbridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christopher M. O’Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marc A. Pfeffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mandeep R. Mehra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Scott D. Solomon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Clyde W. Yancy
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mona Fiuzat
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robert J. Mentz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sean P. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. John J. V. McMurray
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Muthiah Vaduganathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Preston M. Dunnmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Giuseppe M. C. Rosano
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Wilfried Dinh
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Frank Misselwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Robert O. Bonow
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Mihai Gheorghiade
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mihai Gheorghiade.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Harinstein, M.E., Butler, J., Greene, S.J. et al. Site selection for heart failure clinical trials in the USA. Heart Fail Rev 20, 375–383 (2015). https://doi.org/10.1007/s10741-015-9473-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-015-9473-z

Keywords

Search

Navigation