Korean Circ J.  2022 Jun;52(6):401-413. 10.4070/kcj.2022.0100.

Pragmatic Clinical Studies: An Emerging Clinical Research Discipline for Improving Evidence-Based Practice of Cardiovascular Diseases in Asia

• Zhao D
• Yao C

• KMID: 2530445
• DOI: http://doi.org/10.4070/kcj.2022.0100

Abstract

Pragmatic clinical studies, an emerging clinical research discipline, include a wide range of studies that are largely embedded with routine clinical practice and aim to evaluate the comparative effectiveness and safety of different clinical intervention strategies. Increased availability and quality of electronic medical/health records drives the development of pragmatic clinical studies. In this review, we describe evolution of the conceptual framework of pragmatic clinical studies and share perspectives on the importance of pragmatic clinical studies in evidence-based practice for cardiovascular diseases, as a complement to conventional randomized controlled trials. We also highlight specific needs of pragmatic clinical studies in improving evidence-based practice for cardiovascular disease in Asian countries. The main challenges of pragmatic clinical studies are discussed briefly in this review.

Keyword

Pragmatic clinical study; Cardiovascular disease; Asia

Reference

1. Zhao D. Epidemiology features of cardiovascular disease in Asia. JACC-Asia. 2021; 1:1–13.

2. Liu J, Ma C. Current state of cardiovascular research in China. Nat Rev Cardiol. 2019; 16:575–576. PMID: 31399717.

3. U.S. National Library of Medicine. ClinicalTrial.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine;2022. cited 2022 Feburary 15. Available from: https://www.clinicaltrials.gov/.

4. Ford I, Norrie J. Pragmatic trials. N Engl J Med. 2016; 375:454–463. PMID: 27518663.

5. Jones WS, Roe MT, Antman EM, et al. The changing landscape of randomized clinical trials in cardiovascular disease. J Am Coll Cardiol. 2016; 68:1898–1907. PMID: 27765193.

6. Zhou Q, Dong CY, Wang YM, Zhang BH, Cheng YL, Yao C. The role of evidence-based medicine in guiding clinical research and practice expert opinion based on studies on antiviral drugs for the treatment of COVID-19. Chin J Evid Based Med. 2022; 22:373–379.

7. You SC, Rho Y, Bikdeli B, et al. Association of ticagrelor vs clopidogrel with net adverse clinical events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. JAMA. 2020; 324:1640–1650. PMID: 33107944.

8. Anderson CS, Arima H, Lavados P, et al. Cluster-randomized, crossover trial of head positioning in acute stroke. N Engl J Med. 2017; 376:2437–2447. PMID: 28636854.

9. Zhou M, Zhang J, Liu J, et al. Proton pump inhibitors and in-hospital gastrointestinal bleeding in patients with acute coronary syndrome receiving dual antiplatelet therapy. Mayo Clin Proc. 2022; 97:682–692. PMID: 35164933.

10. Shoji S, Sawano M, Sandhu AT, et al. Ischemic and bleeding events among patients with acute coronary syndrome associated with low-dose prasugrel vs standard-dose clopidogrel treatment. JAMA Netw Open. 2020; 3:e202004. PMID: 32239221.

11. Nakamura M, Kadota K, Takahashi A, et al. Relationship between platelet reactivity and ischemic and bleeding events after percutaneous coronary intervention in East Asian patients: 1-year results of the PENDULUM registry. J Am Heart Assoc. 2020; 9:e015439. PMID: 32394794.

12. Zheng B, Huo Y, Lee SW, et al. Long-term antithrombotic management patterns in Asian patients with acute coronary syndrome: 2-year observations from the EPICOR Asia study. Clin Cardiol. 2020; 43:999–1008. PMID: 32618009.

13. Yoon YH, Ahn JM, Kang DY, et al. Pragmatic trial comparing routine versus no routine functional testing in high-risk patients who underwent percutaneous coronary intervention: rationale and design of POST-PCI trial. Am Heart J. 2020; 224:156–165. PMID: 32402702.

14. Zheng Y, Reinhardt JD, Li J, et al. Can clinical and functional outcomes be improved with an intelligent “internet plus”-based full disease cycle remote ischemic conditioning program in acute ST-elevation myocardial infarction patients undergoing percutaneous coronary intervention? Rationale and design of the i-RIC trial. Cardiovasc Drugs Ther. 2022; 36:45–57. PMID: 32607820.

15. Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis. 1967; 20:637–648. PMID: 4860352.

16. Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Clin Epidemiol. 2009; 62:499–505. PMID: 19348976.

17. Sackett DL. Clinical epidemiology: how to do clinical practice research. Philadelphia (PA): Lippincott, Williams and Wilkins;2006.

18. Zwarenstein M, Treweek S, Gagnier JJ, et al. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ. 2008; 337:a2390. PMID: 19001484.

19. Thorpe KE, Zwarenstein M, Oxman AD, et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol. 2009; 62:464–475. PMID: 19348971.

20. Loudon K, Treweek S, Sullivan F, Donnan P, Thorpe KE, Zwarenstein M. The PRECIS-2 tool: designing trials that are fit for purpose. BMJ. 2015; 350:h2147. PMID: 25956159.

21. Kwakkenbos L, Imran M, McCall SJ, et al. CONSORT extension for the reporting of randomised controlled trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE): checklist with explanation and elaboration. BMJ. 2021; 373:n857. PMID: 33926904.

22. Evans RS. Electronic health records: then, now, and in the Future. Yearb Med Inform. 2016; 25(Suppl 1):S48–S61.

23. Hemingway H, Asselbergs FW, Danesh J, et al. Big data from electronic health records for early and late translational cardiovascular research: challenges and potential. Eur Heart J. 2018; 39:1481–1495. PMID: 29370377.

24. Antman EM, Bierer BE. Standards for clinical research: keeping pace with the technology of the future. Circulation. 2016; 133:823–825. PMID: 26927004.

25. Djulbegovic B, Guyatt GH. Progress in evidence-based medicine: a quarter century on. Lancet. 2017; 390:415–423. PMID: 28215660.

26. Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA. 2009; 301:831–841. PMID: 19244190.

27. Guyatt G. Evidence-based medicine. ACP J Club. 1991; 114:A16.

28. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ. 1996; 312:71–72. PMID: 8555924.

29. Fanaroff AC, Fudim M, Califf RM, Windecker S, Smith SC Jr, Lopes RD. Levels of evidence supporting drug, device, and other recommendations in the American Heart Association/American College of Cardiology guidelines. Am Heart J. 2020; 226:4–12. PMID: 32502881.

30. Jneid H, Addison D, Bhatt DL, et al. 2017 AHA/ACC clinical performance and quality measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on performance measures. J Am Coll Cardiol. 2017; 70:2048–2090. PMID: 28943066.

31. Schiele F, Aktaa S, Rossello X, et al. 2020 Update of the quality indicators for acute myocardial infarction: a position paper of the Association for Acute Cardiovascular Care: the study group for quality indicators from the ACVC and the NSTE-ACS guideline group. Eur Heart J Acute Cardiovasc Care. 2021; 10:224–233. PMID: 33550362.

32. Lauer MS, Gordon D, Wei G, Pearson G. Efficient design of clinical trials and epidemiological research: is it possible? Nat Rev Cardiol. 2017; 14:493–501. PMID: 28447664.

33. Kostis JB, Dobrzynski JM. Limitations of randomized clinical trials. Am J Cardiol. 2020; 129:109–115. PMID: 32560898.

34. Laursen PN, Holmvang L, Lønborg J, et al. Comparison between patients included in randomized controlled trials of ischemic heart disease and real-world data. A nationwide study. Am Heart J. 2018; 204:128–138. PMID: 30103092.

35. Smyth B, Haber A, Trongtrakul K, et al. Representativeness of randomized clinical trial cohorts in end-stage kidney disease: a meta-analysis. JAMA Intern Med. 2019; 179:1316–1324. PMID: 31282924.

36. Jackson MW, Austin D, Swanson N, et al. Outcomes after culprit-only percutaneous coronary intervention for multivessel disease during ST-segment elevation myocardial infarction: a comparison of registry and clinical trial outcomes. Coron Artery Dis. 2018; 29:564–572. PMID: 29944476.

37. Megaly M, Buda K, Alaswad K, et al. Comparative analysis of patient characteristics in cardiogenic shock studies: differences between trials and registries. JACC Cardiovasc Interv. 2022; 15:297–304. PMID: 35144785.

38. Hordijk-Trion M, Lenzen M, Wijns W, et al. Patients enrolled in coronary intervention trials are not representative of patients in clinical practice: results from the Euro Heart Survey on Coronary Revascularization. Eur Heart J. 2006; 27:671–678. PMID: 16423872.

39. Franzone A, Heg D, Räber L, et al. External validity of the “all-comers” design: insights from the BIOSCIENCE trial. Clin Res Cardiol. 2016; 105:744–754. PMID: 27033859.

40. Hanlon P, Corcoran N, Rughani G, et al. Observed and expected serious adverse event rates in randomised clinical trials for hypertension: an observational study comparing trials that do and do not focus on older people. Lancet Healthy Longev. 2021; 2:e398–e406. PMID: 34240062.

41. He J, Morales DR, Guthrie B. Exclusion rates in randomized controlled trials of treatments for physical conditions: a systematic review. Trials. 2020; 21:228. PMID: 32102686.

42. Fanaroff AC, Califf RM, Windecker S, Smith SC Jr, Lopes RD. Levels of evidence supporting American College of Cardiology/American Heart Association and European Society of Cardiology Guidelines, 2008–2018. JAMA. 2019; 321:1069–1080. PMID: 30874755.

43. Barnett AS, Lewis WR, Field ME, et al. Quality of evidence underlying the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines on the management of atrial fibrillation. JAMA Cardiol. 2017; 2:319–323. PMID: 28002833.

44. Fröbert O, Lagerqvist B, Olivecrona GK, et al. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med. 2013; 369:1587–1597. PMID: 23991656.

45. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014; 35:2541–2619. PMID: 25173339.

46. Franklin JM, Patorno E, Desai RJ, et al. Emulating randomized clinical trials with nonrandomized real-world evidence studies: first results from the RCT DUPLICATE initiative. Circulation. 2021; 143:1002–1013. PMID: 33327727.

47. Baumfeld Andre E, Reynolds R, Caubel P, Azoulay L, Dreyer NA. Trial designs using real-world data: the changing landscape of the regulatory approval process. Pharmacoepidemiol Drug Saf. 2020; 29:1201–1212. PMID: 31823482.

48. Li M, Chen S, Lai Y, et al. Integrating real-world evidence in the regulatory decision-making process: a systematic analysis of experiences in the US, EU, and China using a logic model. Front Med (Lausanne). 2021; 8:669509. PMID: 34136505.

49. Nishioka K, Makimura T, Ishiguro A, Nonaka T, Yamaguchi M, Uyama Y. Evolving acceptance and use of RWE for regulatory decision making on the benefit/risk assessment of a drug in Japan. Clin Pharmacol Ther. 2022; 111:35–43. PMID: 34528701.

50. Chiang CE, Wang KL, Lip GY. Stroke prevention in atrial fibrillation: an Asian perspective. Thromb Haemost. 2014; 111:789–797. PMID: 24500243.

51. Levine GN, Jeong YH, Goto S, et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol. 2014; 11:597–606. PMID: 25154978.

52. Huo Y, Jeong YH, Gong Y, et al. 2018 update of expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Sci Bull (Beijing). 2019; 64:166–179.

53. Kim HK, Tantry US, Smith SC Jr, et al. The East Asian paradox: an updated position statement on the challenges to the current antithrombotic strategy in patients with cardiovascular disease. Thromb Haemost. 2021; 121:422–432. PMID: 33171520.

54. Kang J, Kim HS. The evolving concept of dual antiplatelet therapy after percutaneous coronary intervention: focus on unique feature of East Asian and “Asian Paradox”. Korean Circ J. 2018; 48:537–551. PMID: 29968428.

55. Cho IY. Using non-vitamin K oral anticoagulants in specific patient populations: a study of Korean cases. Ther Clin Risk Manag. 2019; 15:1183–1206. PMID: 31632045.

56. Cho IY, Choi KH, Sheen YY. How does “Regulatory Practice” create discrepancies in drug label information between Asian and Western countries? Different label information for direct oral anticoagulants approved in the United States, Europe, Korea, and Japan. Ther Innov Regul Sci. 2019; 53:233–242. PMID: 29888622.

57. Bang OY, Hong KS, Heo JH. Asian patients with stroke plus atrial fibrillation and the dose of non-vitamin K oral anticoagulants. J Stroke. 2016; 18:169–178. PMID: 27170995.

58. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013; 34:1279–1291. PMID: 23444397.

59. Lin JL, Chen PS, Lin HW, Tsai LM, Lin SH, Li YH. Real-world analyses of the safety outcome among a general population treated with statins: an Asian population-based study. J Atheroscler Thromb. 2021; 28:63076.

60. Joint Committee for Guideline Revision. 2016 Chinese guidelines for the management of dyslipidemia in adults. J Geriatr Cardiol. 2018; 15:1–29. PMID: 29434622.

61. Daccache C, Rizk R, Dahham J, Evers SM, Hiligsmann M, Karam R. Economic evaluation guidelines in low- and middle-income countries: a systematic review. Int J Technol Assess Health Care. 2021; 38:e1. PMID: 34931601.

62. French C, Pinnock H, Forbes G, Skene I, Taylor SJ. Process evaluation within pragmatic randomised controlled trials: what is it, why is it done, and can we find it? - a systematic review. Trials. 2020; 21:916. PMID: 33168067.

63. Sun X, Tan J, Tang L, Guo JJ, Li X. Real world evidence: experience and lessons from China. BMJ. 2018; 360:j5262. PMID: 29437644.

64. Xie J, Wu EQ, Wang S, et al. Real-world data for healthcare research in China: call for actions. Value Health Reg Issues. 2022; 27:72–81. PMID: 34844062.

65. Bosdriesz JR, Stel VS, van Diepen M, et al. Evidence-based medicine-When observational studies are better than randomized controlled trials. Nephrology (Carlton). 2020; 25:737–743. PMID: 32542836.

66. Benedetto U, Head SJ, Angelini GD, Blackstone EH. Statistical primer: propensity score matching and its alternatives. Eur J Cardiothorac Surg. 2018; 53:1112–1117. PMID: 29684154.

67. Mansournia MA, Altman DG. Inverse probability weighting. BMJ. 2016; 352:i189. PMID: 26773001.

68. Lousdal ML. An introduction to instrumental variable assumptions, validation and estimation. Emerg Themes Epidemiol. 2018; 15:1. PMID: 29387137.