Skip to main content
SpringerLink
Log in

Interpretation of Clinical Trials in the Context of Personalized/Individualized Medicine and End of Life Issues

  • Chapter
  • First Online:
Heart Failure

Part of the book series: Cardiovascular Medicine ((CVM))

  • 2580 Accesses

Abstract

Randomized controlled trials (RCT) provide evidence based medicine that has substantially improved prognosis, symptoms and quality of life of patients with chronic heart failure. Most importantly, negative RCT have stopped super fluent or even harmful therapies. Recent trials have however required thousands of patients to achieve statistical significance. In heart failure, variable etiologies, the manifestation as systolic or diastolic heart failure, chronic stable or acute decompensated heart failure, multiple comorbidities and complications pose a major challenge to clinical studies. For good reasons, many patients have been excluded from trials since their prognosis was foreseeable too good or too fatal. Studies focus on patients with coronary heart disease or non-coronary etiology with variant results. So far, no drug has provided benefit in studies with diastolic heart failure. Nevertheless, most patients with diastolic heart failure are treated with drugs used in systolic heart failure mostly since they are hypertensive. Diuretics are used without evidence of benefit in large trials simply since considered essential for re-compensation in acute heart failure and for fluid control in chronic stable heart failure. The age of our heart failure patients in daily practice is well beyond 70 years, on average 75 years in our INH-registry, and thus older than in most clinical studies. But they are treated as recommended in guidelines based on substantially younger samples. Older patients may have other requirements of therapy. Quality of life out of hospital may be a primary end-point for an aged patient rather than mortality. This may be true also for patients with severe comorbidities, mostly excluded from clinical trials. Standard therapy of diseases failed when they occurred as a comorbidity of heart failure. But can therapy of heart failure be the same in the presence or absence of comorbidity? In a patient with advanced cancer and chemotherapy-induced cardiomyopathy, we would probably be reluctant to recommend an Implantable Cardioverter Defibrillator (ICD). However, heart failure itself may have a similar morbidity and mortality. So what does the mega-trials mean for the individual patient?

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, Huther ML, Richardson DW. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781–8.

    Article  CAS  Google Scholar 

  2. Køber L, Torp-Pedersen C, McMurray JJV, Gøtzsche O, Le’vy S, Crijns H, Amlie J, Carlsen J. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678–87.

    Article  Google Scholar 

  3. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325:1468–75.

    Article  CAS  Google Scholar 

  4. Ertl G, Ruschitzka F. The year in cardiology 2013: heart failure. Eur Heart J. 2014;35:470–3.

    Article  Google Scholar 

  5. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guide lines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;37:2129–200.

    Article  Google Scholar 

  6. Kitzman DW, Rich MW. Age disparities in heart failure research. JAMA. 2010;304:1950–1.

    Article  CAS  Google Scholar 

  7. Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med. 2002;162:1682–8.

    Article  Google Scholar 

  8. Störk S, Hense HW, Zentgraf C, Uebelacker I, Jahns R, Ertl G, Angermann CE. Pharmacotherapy according to treatment guidelines is associated with lower mortality in a community-based sample of patients with chronic heart failure. A prospective cohort study. Eur J Heart Fail. 2008;10:1236–45.

    Article  Google Scholar 

  9. Ertl G, Jugdutt B. ACE inhibition after myocardial infarction: can megatrials provide answers? Lancet. 1994;344:1068–9.

    Article  CAS  Google Scholar 

  10. Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbæk L, Korup E, Jensen G, Hildebrandt P, Steffensen FH, Bruun NE, Eiskjær H, Brandes A, Thøgersen AM, Gustafsson F, Egstrup K, Videbæk R, Hassager C, Svendsen JH, Høfsten DE, Torp-Pedersen C, Pehrson S, DANISH Investigators. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;375:1221–30.

    Article  Google Scholar 

  11. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    Article  CAS  Google Scholar 

  12. Güder G, Frantz S, Bauersachs J, Allolio B, Wanner C, Koller MT, Ertl G, Angermann CA, Störk S. Reverse epidemiology in systolic and non-systolic heart failure: cumulative prognostic benefit of classical cardiovascular risk factors. Circ Heart Fail. 2009;2:563–71.

    Article  Google Scholar 

  13. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G; Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231–9.

    Google Scholar 

  14. Ertl G. Statine bei Herzinsuffizienz. Sinnvoll oder überflüssig? Cardiovasc. 2017;17:37–40.

    Article  Google Scholar 

  15. Angermann CE, Gelbrich G, Störk S, Gunold H, Edelmann F, Wachter R, Schunkert H, Graf T, Kindermann I, Haass M, Blankenberg S, Pankuweit S, Prettin C, Gottwik M, Böhm M, Faller H, Deckert J, Ertl G. Effect of escitalopram on all-cause mortality and hospitalization in patients with heart failure and depression: the MOOD-HF randomized clinical trial. JAMA. 2016;315:2683–93.

    Article  CAS  Google Scholar 

  16. Cowie MR, Woehrle H, Wegscheider K, Angermann C, d’Ortho MP, Erdmann E, Levy P, Simonds AK, Somers VK, Zannad F, Teschler H. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015;373:1095–105.

    Article  CAS  Google Scholar 

  17. Wallenborn J, Marx A, Störk S, Güder G, Brenner S, Ertl G, Angermann CE. Prognostic significance of serial high-sensitivity troponin I measurements following acute cardiac decompensation-correlation with longer-term clinical outcomes and reverse remodelling. Int J Cardiol. 2017;232:199–207.

    Article  Google Scholar 

  18. Arnold JM, Yusuf S, Young J, Mathew J, Johnstone D, Avezum A, Lonn E, Pogue J, Bosch J; HOPE Investigators. Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation. 2003;107:1284–90.

    Article  CAS  Google Scholar 

  19. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, LeWinter MM, Deswal A, Rouleau JL, Ofili EO, Anstrom KJ, Hernandez Ad F, McNulty SE, Velazquez EJ, Kfoury AG, Chen HH, Givertz MM, Semigran MJ, Bart BA, Mascette AM, Braunwald E, O’Connor CMfor the NHLBI Heart Failure Clinical Research Network. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med. 2011;364:797–805.

    Article  CAS  Google Scholar 

  20. Angermann CA, Stoerk S, Gelbrich G, Faller H, Jahns R, Frantz S, Loeffler M, Ertl G. Mode of action and effects of standardized collaborative disease management on mortality and morbidity in patients with systolic heart failure: the interdisciplinary network for heart failure (INH) study. Circ Heart Fail. 2012;5:25–35.

    Article  Google Scholar 

  21. Braunstein JB, Anderson GF, Gerstenblith G, Weller W, Niefeld M, Herbert R, Wu AW. Noncardiac comorbidity increases preventable hospitalizations and mortality among medicare beneficiaries with chronic heart failure. J Am Coll Cardiol. 2003;42:1226–33.

    Article  Google Scholar 

  22. Murray CJL, Lopez AD. Alternative projections of mortality and disability by cause: Global Burden of Disease Study. Lancet. 1997;349:1498–504.

    Article  CAS  Google Scholar 

  23. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML; Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–83.

    Article  Google Scholar 

  24. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJ. More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail. 2001;3:315–22.

    Article  CAS  Google Scholar 

  25. Bekelman DB, Hutt E, Masoudi FA, Kutner JS, Rumsfeld JS. Defining the role of palliative care in older adults with heart failure. Int J Cardiol. 2008;25:183–90.

    Article  Google Scholar 

  26. Dunlay SM, Redfield MM, Weston SA, Therneau TM, Hall Long K, Shah ND, Roger VL. Hospitalizations after heart failure diagnosis a community perspective. J Am Coll Cardiol. 2009;54:1695–702.

    Article  Google Scholar 

  27. Weltgesundheitsorganisation (WHO). WHO definition of palliative care. http://www.who.int/cancer/palliative/definition/en/ (27.03.2013).

  28. Radbruch L, Nauck F, Ostgathe C, Elsner F, Bausewein C, Fuchs M, Lindena G, Neuwöhner K, Schulenberg D. What are the problems in palliative care? Results from a represen- tative survey. Support Care Cancer. 2003;11:442–51.

    Article  Google Scholar 

  29. Goodlin SJ. Palliative care in congestive heart failure. J Am Coll Cardiol. 2009;54:386–96.

    Article  Google Scholar 

  30. Garg R, Yusuf S. Overview of randomized trials of angiotensin converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995;273:1450–6.

    Article  CAS  Google Scholar 

  31. Ertl G. Klinischer Fortschritt: Forschung muss beim Patienten ankommen. Dtsch Med Wochenschr. 2011;136:1993.

    Article  CAS  Google Scholar 

  32. Jaarsma T, Beattie JM, Ryder M, Rutten FH, McDonagh T, Mohacsi P, Murray SA, Grodzicki T, Bergh I, Metra M, Ekman I, Angermann C, Leventhal M, Pitsis A, Anker SD, Gavazzi A, Ponikowski P, Dickstein K, Delacretaz E, Blue L, Strasser F, McMurray J. Advanced Heart Failure Study Group of the HFA of the ESC palliative care in heart failure: a position statement from the palliative care workshop of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2009;11:433–43.

    Article  Google Scholar 

  33. Waltenberger J, Schöne-Seifert B, Friedrich DR, Alt-Epping B, Bestehorn M, Dutzmann J, Ertl G, Fateh-Moghadam B, Israel CW, Maase A. Verantwortlicher Umgang mit ICDs. Stellungnahme der Deutschen Gesellschaft für Kardiologie und ihrer Schwester-Gesellschaften. © Deutsche Gesellschaft für Kardiologie – Herz- und Kreislaufforschung e.V. Published by Springer Medizin Verlag GmbH – all rights reserved 2017. Kardiologe. https://doi.org/10.1007/s12181-017-0185-6.

    Article  Google Scholar 

  34. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure), developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation, endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–235.

    Article  Google Scholar 

  35. Kirkpatrick JN, Gottlieb M, Sehgal P, Patel R, Verdino RJ. Deactivation of implantable cardioverter defibrillators in terminal illness and end of life care. Am J Cardiol. 2012;109:91–4.

    Article  Google Scholar 

  36. Goldstein N, Carlson M, Livote E, Kutner JS. Brief communication: management of implantable cardioverter- defibrillators in hospice: a nationwide survey. Ann Intern Med. 2010;152:296–9.

    Article  Google Scholar 

  37. Marinskis G, van Erven L on behalf of the EHRA Scientific Initiatives Committee. Deactivation of implanted cardioverter-defibrillators at the end of life: results of the EHRA survey. Europace. 2010;12:1176–7.

    Article  Google Scholar 

  38. Padeletti L, Arnar DO, Boncinelli L, Brachman J, Camm JA, Daubert JC, Hassam SK, Deliens L, Glikson M, Hayes D, Israel C, Lampert R, Lobban T, Raatikainen P, Siegal G, Vardas P; Reviewers: Kirchhof P, Becker R, Cosio F, Loh P, Cobbe S, Grace A, Morgan J; European Heart Rhythm Association; Heart Rhythm Society. EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy. Europace. 2010;12:1480–89.

    Article  Google Scholar 

  39. Kramer DB, Ottenberg AL, Gerhardson S, Mueller LA, Kaufman SR, Koenig BA, Mueller PS. “Just Because We Can Doesn’t Mean We Should”: views of nurses on deactivation of pacemakers and implantable cardioverter-defibrillators. J Interv Card Electrophysiol. 2011;32:243–52.

    Article  Google Scholar 

  40. Lingard LA, McDougall A, Schulz V, Shadd J, Marshall D, Strachan PH, Tait GR, Arnold JM, Kimel G. Understanding palliative care on the heart failure care team, an innovative research methodology. J Pain Symptom Manag. 2013;45:901–11.

    Article  Google Scholar 

  41. Rogers JG, Patel CB, Mentz RJ, Granger BB, Steinhauser KE, Fiuzat M, Adams PA, Speck A, Johnson KS, Krishnamoorthy A, Yang H, Anstrom KJ, Dodson GC, Taylor DH Jr, Kirchner JL, Mark DB, O’Connor CM, Tulsky JA. Palliative care in heart failure: the PAL-HF randomized, controlled clinical trial. J Am Coll Cardiol. 2017;70:331–41.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University Hospital and Comprehensive Heart Failure Center (Deutsches Zentrum für Herzinsuffizienz), Würzburg, Germany

    Georg Ertl

Authors
  1. Georg Ertl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Georg Ertl .

Editor information

Editors and Affiliations

  1. Division of Cardiology, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA

    David S. Feldman

  2. Clinic im Park, Cardiovascular Center Zürich, Hirslanden Zurich, Switzerland

    Paul Mohacsi

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ertl, G. (2019). Interpretation of Clinical Trials in the Context of Personalized/Individualized Medicine and End of Life Issues. In: Feldman, D., Mohacsi, P. (eds) Heart Failure. Cardiovascular Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-98184-0_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-98184-0_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-98182-6

  • Online ISBN: 978-3-319-98184-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation