Pragmatic trials-real life studies. Σηέλιορ Λοςκίδηρ MD FCCP Ιαηπική ζσολή ΕΚΠΑ Secretary ERS group 5.2

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2 Pragmatic trials-real life studies Σηέλιορ Λοςκίδηρ MD FCCP Ιαηπική ζσολή ΕΚΠΑ Secretary ERS group 5.2

3 Σσεδιαζμόρ Explanatory vs pragmatic Παραδείγμαηα RCTs PC Pragmatic Αναδρομικές Σχόλια

4 Explanatory vs pragmatic

5 Real life vs explanatory

6 Γιαηί αςξήθηκαν οι real life μελέηερ?

7 Αναδπομική: είναι real life?

8 Σσεδιαζμόρ Explanatory vs pragmatic Παραδείγμαηα RCTs PC Pragmatic Αναδρομικές Σχόλια

9 Ο γνωζηόρ ζσεδιαζμόρ ηηρ ηςσαιοποιημένηρ-διπλήρ ηςθλήρ μελέηηρ

10 Original Article Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein Paul M Ridker, M.D., Eleanor Danielson, M.I.A., Francisco A.H. Fonseca, M.D., Jacques Genest, M.D., Antonio M. Gotto, Jr., M.D., John J.P. Kastelein, M.D., Wolfgang Koenig, M.D., Peter Libby, M.D., Alberto J. Lorenzatti, M.D., Jean G. MacFadyen, B.A., Børge G. Nordestgaard, M.D., James Shepherd, M.D., James T. Willerson, M.D., Robert J. Glynn, Sc.D., for the JUPITER Study Group N Engl J Med Volume 359(21): November 20, 2008

11 As described in detail elsewhere,1men 50 years of age or older and women 60 years of age or older were eligible for the trial if they did not have a history of cardiovascular disease and if, at the initial screening visit, they had an LDL cholesterol level of less than 130 mg per deciliter (3.4 mmol per liter) and a high-sensitivity C-reactive protein level of 2.0 mg per liter or more. Other requirements for inclusion were a willingness to participate for the duration of the trial, provision of written informed consent, and a triglyceride level of less than 500 mg per deciliter (5.6 mmol per liter). Exclusion criteria were previous or current use of lipid-lowering therapy, current use of postmenopausal hormone-replacement therapy, evidence of hepatic dysfunction (an alanine aminotransferase level that was more than twice the upper limit of the normal range), a creatine kinase level that was more than three times the upper limit of the normal range, a creatinine level that was higher than 2.0 mg per deciliter (176.8 μmol per liter), diabetes, uncontrolled hypertension (systolic blood pressure >190 mm Hg or diastolic blood pressure >100 mm Hg), cancer within 5 years before enrollment (with the exception of basal-cell or squamous-cell carcinoma of the skin), uncontrolled hypothyroidism (a thyroid-stimulating hormone level that was more than 1.5 times the upper limit of the normal range), and a recent history of alcohol or drug abuse or another medical condition that might compromise safety or the successful completion of the study. Because a core scientific hypothesis of the trial concerned the role of underlying low-grade inflammation as evidenced by elevated high-sensitivity C-reactive protein levels, patients with inflammatory conditions such as severe arthritis, lupus, or inflammatory bowel disease were excluded, as were patients taking immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, or longterm oral glucocorticoids. All potentially eligible subjects underwent a 4-week run-in phase during which they received placebo. The purpose of this phase was to identify a group of willing and eligible participants who demonstrated good compliance (defined as the taking of more than 80% of all study tablets) during that interval. Only subjects who successfully completed the run-in phase were enrolled.

12 Μελέηη Jupiter: Θα μποπούζε να γίνει reallife? Ridker PM et al. N Engl J Med 2008;359:

13 Πεπαιηέπω ανάλςζη Jupiter Ridker PM et al. N Engl J Med 2008;359:

14 Torch Calverley PMA et al. N Engl J Med 2007;356:

15 Uplift Tashkin DP et al. N Engl J Med 2008;359:

16 CLIMB: Σσεδιαζμόρ μελέηηρ 3-month, double-blind, randomised study R Run-in Treatment period Enrolment Tiotropium 18* µg od Tiotropium 18* µg od + budesonide/formoterol Turbuhaler 320/9* µg bid n = 329 ICS withdrawn visit 1 Enrolled: 990 Randomised: 660 Tiotropium 18* µg od + placebo Turbuhaler bid n = 331 Terbutaline 0.5* mg/dose as reliever Visit: Week: LABA withdrawn < visit 2 *All doses expressed as metered doses Oral and parenteral steroids not used 4 weeks before randomisation

17 Ποπεία ζςμμεηεσόνηων 990 enrolled 660 randomised 330 excluded 209 eligibility criteria not fulfilled 80 voluntary discontinuation 25 adverse event 4 lost to follow-up 2 severe non-compliance 1 safety reasons 9 other reason Run-in (2 weeks) Treatment allocation 331 allocated to TIO + placebo 1 did not receive treatment 28 discontinued 12 voluntary discontinuation 10 adverse event 4 incorrect enrolment 2 other 329 allocated to TIO + Symbicort 0 did not receive treatment 26 discontinued 13 incorrect enrolment 8 adverse event 5 voluntary discontinuation Treatment period (12 weeks) TIO = tiotropium 302 completed 303 completed Study completion

18 Μελέηη Torch: Απώλεια FEV FEV 1 (ml) Control SAL FP SFC 39 ml/yr 42 ml/yr 42 ml/yr 55 ml/yr Time (weeks) Error bars represent 5% and 95% confidence intervals Celli et al. Am J Respir Crit Care Med 2008

19 O πόλορ ηων ICS (EUROSCOP)? 5.3% vs. 3.0% EUROSCOP: a 3-yr, placebo-controlled study Budesonide 800 mg/day in smokers (mean age 52 yrs) with mild COPD n=1,175 patients - 49 (4.2%) patients experienced 60 ischemic cardiac events Lofdahl GC, ERJ 2007; 29:

20 Σηαηίνερ κίνδςνορ πνεςμονίαρ 2012 by Canadian Medical Association Novack V et al. CMAJ 2012;184:E367-E372

21 Σσεδιαζμόρ Explanatory vs pragmatic Παραδείγμαηα RCTs PC Pragmatic Αναδρομικές Σχόλια

22 Original Article Leukotriene Antagonists as First-Line or Add-on Asthma-Controller Therapy David Price, F.R.C.G.P., Stanley D. Musgrave, M.D., Lee Shepstone, Ph.D., Elizabeth V. Hillyer, D.V.M., Erika J. Sims, Ph.D., Richard F.T. Gilbert, M.R.C.G.P., Elizabeth F. Juniper, M.C.S.P., M.Sc., Jon G. Ayres, M.D., Linda Kemp, B.Sc., Annie Blyth, M.A., Edward C.F. Wilson, M.Sc., Stephanie Wolfe, M.Sc., R.G.N., Daryl Freeman, M.R.C.G.P., H. Miranda Mugford, Ph.D., Jamie Murdoch, Ph.D., and Ian Harvey, F.R.C.P. Σύγκριζη LTRA με ICS ζαν μονοθεραπεία και με LABA επιλογή επιπρόζθεηης ζηα ICS N Engl J Med Volume 364(18): May 5, 2011

23 Χαπακηηπιζηικά αηόμων μελέηηρ Price D et al. N Engl J Med 2011;364:

24 Αποηελέζμαηα. Price D et al. N Engl J Med 2011;364:

25 Θεπαπεςηικέρ αλλαγέρ-ζημανηικέρ πληποθοπίερ. Price D et al. N Engl J Med 2011;364:

26 Woodcock A et al. N Engl J Med 2003;349: Μία μελέηη real life..

27 Woodcock A et al. N Engl J Med 2003;349: Real life αποηελέζμαηα

28 Παπακολούθηζη αηόμων μεηά από ιογενή λοίμωξη Antibiotics = 47%; None = 53%; Proportion of patients better by day 3 (P=0.28) Brown D et al JAMA 2010

29 Σσεδιαζμόρ Explanatory vs pragmatic Παραδείγμαηα RCTs PC Pragmatic Αναδρομικές Σχόλια

30 Σηαηίνερ & ACE Mortensen E et al Respiratory Research 2009

31 Θνηζιμόηηηα από πεπιθεπική αγγειακή νόζο: ΧΑΠ & ζηαηίνερ Nussbaumer-Ochsner Y, Rabe K F Chest 2011;139: by American College of Chest Physicians

32 Date of download: 10/3/2012 Copyright American College of Chest Physicians. All rights reserved. From: The Impact of Tiotropium on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting β-agonist Therapy in COPDThe Impact of Tiotropium on COPD CHEST. 2012;141(1): doi: /chest Figure Legend: Kaplan-Meier curve for all-cause mortality. Adjusted hazard ratios calculated using Cox regression. P values calculated with the use of log-rank test. ICS = inhaled corticosteroid; LABA = long-acting β-agonist; Tio = tiotropium.

33 Date of download: 10/3/2012 Copyright American College of Chest Physicians. All rights reserved. From: The Impact of Tiotropium on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting β-agonist Therapy in COPDThe Impact of Tiotropium on COPD CHEST. 2012;141(1): doi: /chest Figure Legend: Kaplan-Meier curve for oral corticosteroid prescription. Adjusted hazard ratios calculated using Cox regression. P values calculated with the use of log-rank test. See Figure 1 legend for expansion of abbreviations.

34 Date of download: 10/3/2012 Copyright American College of Chest Physicians. All rights reserved. From: The Impact of Tiotropium on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting β-agonist Therapy in COPDThe Impact of Tiotropium on COPD CHEST. 2012;141(1): doi: /chest Figure Legend: Kaplan-Meier curve for hospital admission for respiratory disease. Adjusted hazard ratios calculated using Cox regression. P values calculated with the use of log-rank test. See Figure 1 legend for expansion of abbreviations.

35 Σσεδιαζμόρ Explanatory vs pragmatic Παραδείγμαηα RCTs PC Pragmatic Αναδρομικές Σχόλια

36 Σχόλια: Τι ψάχνουμε τελικά? Nallamothu B K et al. Circulation 2008;118: Copyright American Heart Association

37 Statistics in medicine: Pragmatic Trials Guides to Better Patient Care? James H. Ware, Ph.D., and Mary Beth Hamel, M.D., M.P.H. NEJM 2011 Although randomized clinical trials provide essential, high-quality evidence about the benefits and harms of medical interventions, many such trials have limited relevance to clinical practice Pragmatic trials are designed to study real-world practice and therefore represent less-perfect experiments than efficacy trials; they sacrifice internal validity. An explanatory clinical trial is the best way to assess whether an intervention works, but arguably the worst way to assess who will benefit

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