1. G. Biondi Zoccai – Ricerca in cardiologia RICERCA CLINICA IN CARDIOLOGIA INTERVENTISTICA (2/2) Percorso didattico basato sulla revisione ed interpretazione dei dati derivanti dalla letteratura scientifica Giuseppe Biondi Zoccai, Divisione di Cardiologia 1, Ospedale S. Giovanni Battista “Molinette”, Torino gbiondizoccai@gmail.com – http://www.metcardio.org gbiondizoccai@gmail.comhttp://www.metcardio.org

2. G. Biondi Zoccai – Ricerca in cardiologia What to expect? Core modules IntroductionIntroduction Finding out relevant literatureFinding out relevant literature General guidelines for literature appraisalGeneral guidelines for literature appraisal Abstract and Introduction appraisalAbstract and Introduction appraisal Methods and Results appraisal 1 - Patients and proceduresMethods and Results appraisal 1 - Patients and procedures Methods and Results appraisal 2 - Data collection/management and descriptive analysisMethods and Results appraisal 2 - Data collection/management and descriptive analysis Methods and Results appraisal 3 - Inferential analysisMethods and Results appraisal 3 - Inferential analysis Discussion and Conclusions appraisalDiscussion and Conclusions appraisal

3. G. Biondi Zoccai – Ricerca in cardiologia Topics of this presentation Study designStudy design Patient characterizationPatient characterization ProceduresProcedures Follow-upFollow-up End-pointsEnd-points Additional analysesAdditional analyses

4. G. Biondi Zoccai – Ricerca in cardiologia Topics of this presentation Study designStudy design Patient characterizationPatient characterization ProceduresProcedures Follow-upFollow-up End-pointsEnd-points Additional analysesAdditional analyses

5. G. Biondi Zoccai – Ricerca in cardiologia Study design The study design should be clearly stated either in the end of the Introduction, or in the Methods BEWARE IF IT IS NOT CLEARLY STATED! Focus on prospective vs retrospective designFocus on prospective vs retrospective design Clarify whether the study was single or multicenterClarify whether the study was single or multicenter Is the study beneficial to any third party (eg sponsor)? If yes, assess whether it was spontaneous or funded, and whether any conflict of interest is presentIs the study beneficial to any third party (eg sponsor)? If yes, assess whether it was spontaneous or funded, and whether any conflict of interest is present Remember, not telling the whole truth is much more common than telling lies, but nonetheless may be done on purpose to fool the readers!

6. G. Biondi Zoccai – Ricerca in cardiologia Study design Ardissino JAMA 2004

7. G. Biondi Zoccai – Ricerca in cardiologia Topics of this presentation Study designStudy design Patient selection/characterizationPatient selection/characterization ProceduresProcedures Follow-upFollow-up End-pointsEnd-points Additional analysesAdditional analyses

8. G. Biondi Zoccai – Ricerca in cardiologia Patients Clear statements on the selection of patients are pivotal to explicitly identify the target population BEWARE IF THEY ARE NOT CLEARLY STATED! Focus on inclusion vs exclusion criteriaFocus on inclusion vs exclusion criteria Focus on consecutive vs purposeful enrolmentFocus on consecutive vs purposeful enrolment Is the patient population highly selected or are they everyday subjects?Is the patient population highly selected or are they everyday subjects? Do authors provide separate numbers of patients screened, enrolled and randomizedDo authors provide separate numbers of patients screened, enrolled and randomized Remember, a highly selected population will provide more internally valid answers, but at the price of lower external validity

9. G. Biondi Zoccai – Ricerca in cardiologia Patients Ardissino JAMA 2004

10. G. Biondi Zoccai – Ricerca in cardiologia Patients

11. Patients Biondi Zoccai Ital Heart J 2003

12. G. Biondi Zoccai – Ricerca in cardiologia Topics of this presentation Study designStudy design Patient selection/characterizationPatient selection/characterization ProceduresProcedures Follow-upFollow-up End-pointsEnd-points Additional analysesAdditional analyses

13. G. Biondi Zoccai – Ricerca in cardiologia Procedures Clear statements on the interventional procedures are pivotal to ensure reproducibility of outcomes BEWARE IF THEY ARE NOT CLEARLY STATED! Focus on technical aspects, devices, and safety measuresFocus on technical aspects, devices, and safety measures Additional therapies are important as well (eg thienopyridines)Additional therapies are important as well (eg thienopyridines) Can the techniques described be reasonably performed in other cath labs with the available equipments and expertise?Can the techniques described be reasonably performed in other cath labs with the available equipments and expertise? Do authors provide accurate data on the management of all scenarios (even the worst case one)?Do authors provide accurate data on the management of all scenarios (even the worst case one)? Remember, centers with a specific expertise in a technique or device might provide results that are not easily reproducible by others

14. G. Biondi Zoccai – Ricerca in cardiologia Procedures Ardissino JAMA 2004

15. G. Biondi Zoccai – Ricerca in cardiologia Procedures

16. Procedures Colombo CCI 2005

17. G. Biondi Zoccai – Ricerca in cardiologia Topics of this presentation Study designStudy design Patient selection/characterizationPatient selection/characterization ProceduresProcedures Follow-upFollow-up End-pointsEnd-points Additional analysesAdditional analyses

18. G. Biondi Zoccai – Ricerca in cardiologia Follow-up Follow-up procedures should be standardized and equally applied to all relevant patient groups Focus on follow-up techniques (eg lab tests, ECG, phone interview, office visit,…)Focus on follow-up techniques (eg lab tests, ECG, phone interview, office visit,…) Clearly identify follow-up duration (mean, median, standard deviation, range,…). Is it similar in the groups being compared?Clearly identify follow-up duration (mean, median, standard deviation, range,…). Is it similar in the groups being compared? Was enrolment going over for a long time or limited to a brief time frame?Was enrolment going over for a long time or limited to a brief time frame? Were there drop-outs, drop-ins, non-compliant pts, or losses to follow- up?Were there drop-outs, drop-ins, non-compliant pts, or losses to follow- up? Remember, for clinical studies a >95% follow-up is mandatory to limit the risk of attrition bias

19. G. Biondi Zoccai – Ricerca in cardiologia Follow-up Holmes JAMA 2006

20. G. Biondi Zoccai – Ricerca in cardiologia Follow-up Holmes JAMA 2006

21. G. Biondi Zoccai – Ricerca in cardiologia Follow-up Ardissino JAMA 2004

22. G. Biondi Zoccai – Ricerca in cardiologia Topics of this presentation Study designStudy design Patient selection/characterizationPatient selection/characterization ProceduresProcedures Follow-upFollow-up End-pointsEnd-points Additional analysesAdditional analyses

23. G. Biondi Zoccai – Ricerca in cardiologia End-points Clear statements on the primary, secondary, and additional end-points are paramount. In case of doubt, remain skeptical! BEWARE OF SECONDARY END-POINTS OR SUB-GROUP ANALYSES! Focus on the primary end-point, as this was the only one for which the study was truly poweredFocus on the primary end-point, as this was the only one for which the study was truly powered Check for spurious inconsistencies between primary vs secondary or efficacy vs safety end-pointsCheck for spurious inconsistencies between primary vs secondary or efficacy vs safety end-points Were outcome assessors unaware of treatment assignment?Were outcome assessors unaware of treatment assignment? Sub-group analyses are by definition (unless otherwise stated) hypothesis-generating. In any case, the risks of alpha error and biological non-plausibility applySub-group analyses are by definition (unless otherwise stated) hypothesis-generating. In any case, the risks of alpha error and biological non-plausibility apply

24. G. Biondi Zoccai – Ricerca in cardiologia End-points Ardissino JAMA 2004

25. G. Biondi Zoccai – Ricerca in cardiologia End-points Holmes JAMA 2006

26. G. Biondi Zoccai – Ricerca in cardiologia End-points

27. Topics of this presentation Study designStudy design Patient selection/characterizationPatient selection/characterization ProceduresProcedures Follow-upFollow-up End-pointsEnd-points Additional analysesAdditional analyses

28. G. Biondi Zoccai – Ricerca in cardiologia Additional analyses Additional analyses (eg, QCA, IVUS, TIMI flow, troponin release) are important in that they may drive the primary end-point (eg, TLR) or substantiate it indirectly (eg TIMI flow) Focus on technical aspects, devices, software and reproducibilityFocus on technical aspects, devices, software and reproducibility Was personnel involved in additional analyses unaware of treatment assignment?Was personnel involved in additional analyses unaware of treatment assignment? Beware of tautology issuesBeware of tautology issues Some studies may indeed have more a pathophysiological than a clinical edgeSome studies may indeed have more a pathophysiological than a clinical edge Remember that additional analyses should be distinguished from cosmetic analyses

29. G. Biondi Zoccai – Ricerca in cardiologia Additional analyses

30. G. Biondi Zoccai – Ricerca in cardiologia Additional analyses Windecker NEJM 2005