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Advantages and Disadvantages in Clinical Trials

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Management of Hypertension

Abstract

Describing the strengths and limitations of clinical trials in a chapter of this book is difficult because of the complexity of the issues, the large number of relevant publications and the accelerating rate of new developments in the field. For these reasons, this chapter is somewhat eclectic in including important items especially those pertaining to current developments. Making clinical decisions on individual patients after consideration of all strengths and limitations of clinical trials is difficult. As Hippocrates stated in the Aphorisms, Life is short, and art long, opportunity fleeting, experience misleading, and judgment difficult. Ὁ βίος βραχύς, ἡ δὲ τέχνη μακρή, ὁ δὲ καιρὸς ὀξύς, ἡ δὲ πεῖρα σφαλερή, ἡ δὲ κρίσις χαλεπή. Clinical trials are essential in establishing the efficacy of pharmacologic and other interventions, but it may be difficult to make decisions on individual patients since the trials include large numbers of participants.

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References

  1. Hippocrates. In: Adams CD, editor. The genuine works of Hippocrates. New York: Dover; 1868.

    Google Scholar 

  2. Fisher RA, Mackenzie WA. Studies in crop variation. II. The manorial response of different potato varieties. J Agric Sci. 1923;13:311–20.

    Article  Google Scholar 

  3. Fisher RA. On the “probable error” of a coefficient of correlation deduced from a small sample. Metro. 1921;1:3–32.

    Google Scholar 

  4. Bhatt A. Evolution of clinical research: a history before and beyond James Lind. PICR. 2010;1(1):6–10.

    Google Scholar 

  5. Collier R. Legumes, lemons and streptomycin: a short history of the clinical trial. CMAJ. 2009;180:23–4.

    Article  Google Scholar 

  6. MRC Streptomycin in Tuberculosis Trials Committee. Streptomycin treatment of pulmonary tuberculosis. BMJ. 1948;2:769–83.

    Article  Google Scholar 

  7. Hart PD. A change in scientific approach: from alternation to randomised allocation in clinical trials in the 1940s. BMJ. 1999;319(7209):572–3.

    Article  Google Scholar 

  8. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med. 1991;325(11):756–62.

    Article  CAS  Google Scholar 

  9. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy post-menopausal women. Principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–33.

    Article  Google Scholar 

  10. Loken E, Gelman A. Measurement error and the replication crisis. Science. 2017;355(6325):584–5.

    Article  CAS  Google Scholar 

  11. Veterans Administration Cooperative Study Group on Anti-hypertensive Agents. Effects of treatment on morbidity and mortality in hypertension: I. Results in patients with diastolic blood pressure averaging 115–129 mm Hg. JAMA. 1967;202:116–22.

    Article  Google Scholar 

  12. Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ACPM/AphA/ASH/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13–e115.

    Google Scholar 

  13. Blood Pressure Lowering Treatment Trialists’ Collaboration, Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25(5):951–8. Erratum in: J Hypertens. 2007;25(7):1524.

    Article  Google Scholar 

  14. Hill AB. Principles of medical statistics. Lancet. 1937;229:706–8.

    Article  Google Scholar 

  15. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bothwell LE, Podolsky SH. The emergence of the randomized, controlled trial. N Engl J Med. 2016;375:501–4.

    Article  Google Scholar 

  17. Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet. 2002;359(9302):248–52.

    Article  Google Scholar 

  18. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–6.

    Article  CAS  Google Scholar 

  19. Parsa A, Brown E, Weir MR, et al. Genotype-based changes in serum uric acid affect blood pressure. Kidney Int. 2012;81:502–7.

    Article  CAS  Google Scholar 

  20. Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503–12.

    Article  CAS  Google Scholar 

  21. Frieden TR. Evidence for health decision-making – beyond randomized, controlled trials. N Engl J Med. 2017;377:465–75.

    Article  Google Scholar 

  22. Treweek S, Zwarenstein M. Making trials matter: pragmatic and explanatory trials and the problem of applicability. Trials. 2009;10:37. https://doi.org/10.1186/1745-6215-10-37.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Mauri L, D’Agostino RB Sr. Challenges in the design and interpretation of noninferiority trials. N Engl J Med. 2017;377:1357–67.

    Article  Google Scholar 

  24. Steinhubl SR, McGovern P, Dylan J, Topol EJ. The digitised clinical trial. Lancet. 2017;390(10108):2135. https://doi.org/10.1016/S0140-6736(17)32741-1. Epub 2017 Nov 9.

    Article  PubMed  Google Scholar 

  25. Steinhubl SR, Muse ED, Topol EJ. The emerging field of mobile health. Sci Transl Med. 2015;7(283):283rv3. https://doi.org/10.1126/scitranslmed.aaa3487.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lauer MS, Krumholz HM, Topol EJ. Time for a prepublication culture in clinical research? Lancet. 2015;386(10012):2447–9.

    Article  Google Scholar 

  27. Nochomovitz M, Sharma R. Is it time for a new medical specialty?: The medical virtualist. JAMA. 2018;319(5):437–8.

    Article  Google Scholar 

  28. Grady C. Enduring and emerging challenges of informed consent. N Engl J Med. 2015;372:855–62.

    Article  CAS  Google Scholar 

  29. Grady C, Cummings SR, Rowbotham MC, McConnell MV, Ashley EA, Kang G. Informed consent. N Engl J Med. 2017;376:856–67.

    Article  Google Scholar 

  30. Basu S, Sussman JB, Hayward RA. Detecting heterogeneous treatment effects to guide personalized blood pressure treatment: a modeling study of randomized clinical trials. Ann Intern Med. 2017;166(16695):354–60.

    Article  Google Scholar 

  31. Kostis JB. Meta-analysis, meta-regression, and meta-physics. JCH. 2003;1:64–5.

    Google Scholar 

  32. Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. JACC. 2012;59:572–82.

    Article  CAS  Google Scholar 

  33. Cornell JE, Liao JM, Stack CB, Mulrow CD. Annals understanding clinical research: evaluating the meaning of a summary estimate in a meta-analysis. Ann Intern Med. 2017;167(4):275–7.

    Article  Google Scholar 

  34. Kostis JB, Davis BR, Cutler J, for the SHEP Cooperative Research Group, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1997;278:212–6.

    Article  CAS  Google Scholar 

  35. Franklin B, Bailly JS, Lavoisier A. Chez Gabliel Floteron, Nice. Papport des commissaires decharges par le Roi a l’examen du magnetisme animal 1785.

    Google Scholar 

  36. Vazire S. Our obsession with eminence warps research. Nature. 2017;547(7661):7.

    Article  CAS  Google Scholar 

  37. Little R, Yau L. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics. 1996;52(4):1324–33.

    Article  CAS  Google Scholar 

  38. Al-Lemee R, Thompson DHM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomized controlled trial. Lancet. 2018;391:31–40.

    Google Scholar 

  39. Coronary Drug Project Research Group. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med. 1980;303(18):1038–41.

    Article  Google Scholar 

  40. Murray EJ, Herman MA. Adherence adjustment in the Coronary Drug Project: a call for better per-protocol effect estimates in randomized trials. Clin Trials. 2016;13:372–8.

    Article  Google Scholar 

  41. Gupta A, Thompson D, Whitehouse A, Collier T, ASCOT Investigators, et al. Adverse events associated with unblended, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomized double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017;389(10088):2473–81.

    Article  CAS  Google Scholar 

  42. Attia J, Page J. A graphic framework for teaching critical appraisal of randomized controlled trials. ACP J Club. 2001;134(4):A11–2.

    CAS  PubMed  Google Scholar 

  43. Rosenblatt M. The large pharmaceutical company perspective. N Engl J Med. 2017;376(1):52–60.

    Article  Google Scholar 

  44. Xue L, Meng X, Timofeeva M, et al. Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies. BMJ. 2017;357:j2376.

    Google Scholar 

  45. Breznau N. Secondary observer effects: idiosyncratic errors in small-N secondary data analysis. Int J Soc Res Methodol. 2016;19:301–18.

    Article  Google Scholar 

  46. Hawthorne Effect. Wikipedia accessed January 15, 2017.

    Google Scholar 

  47. Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized clinical trials good for us (in the short term)? Evidence for a “trial effect”. J Clin Epidemiol. 2001;54(3):217–24.

    Article  CAS  Google Scholar 

  48. Kostis WJ, Cabrera J, Messerli FH, Cheng JQ, Sedjro JE, Cosgrove NM, et al. Competing cardiovascular and noncardiovascular risks and longevity in the Systolic Hypertension in the Elderly Program. Am J Cardiol. 2014;113(4):676–81.

    Article  Google Scholar 

  49. Aspirin Myocardial Infarction Study Research Group. A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA. 1980;243:661–9.

    Article  Google Scholar 

  50. Poynard T, Munteanu M, Ratziu V. Truth survival in clinical research: an evidence-based requiem? Ann Intern Med. 2002;136:888–95.

    Article  Google Scholar 

  51. Mark DB, Lee KL, Harrell FE Jr. Understand the role of p values and hypothesis tests in clinical research. JAMA Cardiol. 2016;1(9):1048–54.

    Article  Google Scholar 

  52. Wasserstein RL, Lazar NA. The ASA’s statement on p-values: context, process, and purpose. Am Stat. 2016;70:129–33.

    Article  Google Scholar 

  53. Lee J, McShane BB, Gelman A, Colquhoun D, Nuijten MB, Goodman SN. Five ways to fix statistics. Nature. 2017;551:557–9.

    Article  Google Scholar 

  54. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351(6):543–51.

    Article  CAS  Google Scholar 

  55. Sever PS, Poulter NR, Dahlof B, ASCOT Investigators, et al. The Anglo-Scandinavian Cardiac Outcomes Trial lipid lowering arm: extended observations 2 years after trial closure. Eur. Heart. 2008;29(4):499–508.

    Article  CAS  Google Scholar 

  56. Kostis WJ, Thijs L, Richart T, Kostis JB, Staessen JA. Persistence of mortality reduction after the end of randomized therapy in clinical trials of blood pressure lowering medications. Hypertension. 2010;56:1060–8.

    Article  CAS  Google Scholar 

  57. van der Lee JH, Wesseling J, Tanck MW, Offringa M. Efficient ways exist to obtain the optimal sample size in clinical trials in rare diseases. J Clin Epidemiol. 2008;61(4):324–30.

    Article  Google Scholar 

  58. Karrison TG, Huo D, Chappell R. A group sequential, response-adaptive design for randomized clinical trials. Control Clin Trials. 2003;24(5):506–22.

    Article  Google Scholar 

  59. Horton R. The clinical trial: deceitful, disputable, unbelievable, unhelpful, and shameful-what next? Control Clin Trials. 2001;22:593–604.

    Article  CAS  Google Scholar 

  60. Weiss R. Nip misinformation in the bud. Science. 2017;358(6362):427.

    Article  CAS  Google Scholar 

  61. Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B. Placebo-controlled trials and the declaration of Helsinki. Lancet. 2002;359(9314):1337–40.

    Article  Google Scholar 

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Kostis, W.J., Dobrzynski, J.M., Kostis, J.B. (2019). Advantages and Disadvantages in Clinical Trials. In: Papademetriou, V., Andreadis, E., Geladari, C. (eds) Management of Hypertension. Springer, Cham. https://doi.org/10.1007/978-3-319-92946-0_12

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  • DOI: https://doi.org/10.1007/978-3-319-92946-0_12

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