RRCT. Registry-based Randomized Clinical Trials. Svein Rotevatn Faglig leder Norsk Register for Invasiv Kardiologi

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Stian Abrahamsen
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1 RRCT Registry-based Randomized Clinical Trials Svein Rotevatn Faglig leder Norsk Register for Invasiv Kardiologi

2 Diclosures / interessekonflikter: Behandler pasienter med trange/tette kransårer for å åpne disse ved hjerteinfarkt eller angina ikke statistiker, men tror på statistikk Faglig leder for Norsk Register for invasiv kardiologi Lege, spesialist i indremedisin og hjertesykdommer

3 Grunnleggende spørsmål Gir jeg pasientene mine den beste behandlingen de kan få? Hvordan kan jeg være sikker på det?

4 Grunnleggende spørsmål Gir jeg pasientene mine den beste behandlingen de kan få? Hvordan kan jeg være sikker på det? SVAR: Sjekke om behandlingen er i samsvar med siste forskningsresultater!!

5 Siste forskningsresultater.. Søk i PubMed artikler om STEMI 1910 artikler i artikler om klaffesykdom 3147 artikler i artikler i 2017 om behandling av klaffesykdom

6 Siste forskningsresultater.. Søk i PubMed artikler om STEMI 1910 artikler i artikler om klaffesykdom 3147 artikler i artikler i 2017 om behandling av klaffesykdom En umulig oppgave!?

7 Forskning for å sammenligne ulik behandling Utfordring: Faktorer som påvirker valg av behandling hos lege og pasient Ubalanse i bakgrunnsvariabler mellom behandlingsgruppene Confounders

8 Eksempel: kolesterosenkende behandling før pasienten får hjerteinfarkt

9 Eksempel: kolesterosenkende behandling før pasienten får hjerteinfarkt Ikke kontroll for forskjeller i alder median alder statin behandl. 62 år ikke statin behandl. 66 år Allerede syke har større sannsynlighet for å ha kolesterolsenkende behandling

10 MA Hlatky: Heart Fail Clin (1):

13 Guidelines Sammendrag laget av eksperter Oppsummerer fagfeltet

17 by Ole Fröbert, MD, PhD, FESC

18 H.Han et al. J Am Coll Cardiol 2015;65:

19 Summary. so far A) Clinical decision needs evidence B) Evidence obtained by i. Experiment (RCTs) ii. Observation (Registries) iii. Opinion (Experts) C) RCTs are required but scarce

20 Summary. so far A) Clinical decision needs evidence B) Evidence obtained by i. Experiment (RCTs) ii. Observation (Registries) iii. Opinion (Experts) C) RCTs are required but scarce D) RRCTs may be part of a solution?

21 RRCT = Registry + RCT Prospective randomized trial that uses a clinical registry for one or several major functions for trial conduct and outcomes reporting.

22 Source: Stefan James

26 TAPAS / Swedish registry data TA+PCI (N=3 666) PCI alone (N=16 417) HR (95% CI): 1.21 ( ) Vlaar, P.J. et al. The Lancet 2008; 371: Fröbert, O. et al. Int J Cardiol. 2010; 145:572-3

36 RRCT STUDY MANAGMENT DATABASE SCREENING LOG SCREENING LOG REGISTRY SUBJECT LOG SUBJECT LOG RRCT STUDY DATABASE

38 Background: Full revascularization in STEMI patients with multivessel disease Three small studies (PRAMI, CvLPRIT and PRIMULTI) reduction in composite clinical endpoints repeat revascularization or refractory angina no trial has been powered for hard clinical endpoints to change guidelines. Hypothesis: complete revascularization of non-culprit lesions with FFR-guided PCI following primary PCI for acute STEMI/high risk NSTEMI leads to improved clinical outcomes at one year compared to initial conservative management.

39 Inclusion criteria: STEMI or very high risk NSTEMI (dynamic STT changes, or ongoing chest pain or hemodynamic instability independent of ECG changes or life-threatening ventricular arrythmias). Exclusion criteria: Previous CABG, left main disease, shock. Primary endpoint: All-cause mortality + Myocardial Infarction Key secondary endpoint: Unplanned revascularization (PCI/CABG)

40 Study design: Multicentre international registry-based randomized controlled clinical trial based on SCAAR and NORIC or Electronic Data Capture with a potential of a high inclusion rate, low bias and complete follow-up of events at a low cost. Adjudication: All MI and revascularization procedures will be adjudicated by independent reviewers at the clinical events adjudication committee. Clinically relevant effect size: 25% RRR and two-sided test with p level 5% Sample size: 4052 subjects for alpha 0.05 and beta 0.8, 1:1 allocation Estimated population: STEMI per annum

42 Registry follow-up Description in the protocol Approval by REC / IRB Informed consent

43 Registry follow-up Screening log No directly identifiable variables Very limited indirectly identifiable variables Subject log Patients with consent Randomization group Baseline and procedure characteristics Study specific varables Detection of clinical endpoints

44 Screening log Name Definition Type Comments CORRELATION_ID PERSONAL_IDENTITY_NUMBER PIN_ISSUING_ENTITY SCREENING_TIME SCREENING_TIME_ZONE_ID SITE_ID INVESTIGATOR_ID ID of the PCI registration for which the screening was done External identity of the screened person Identifier for the entity that has issued the personal identity number Instant when the screening was saved Time zone for the instant where the screening was saved ID of the Site that did the screening ID of the Investigator that did the screening Text Text [SE, NO, DK, IS] Instant (date and time) Text Text Text In non-swedish countries this will be populated with a random number In non-swedish countries this will be populated with a random number Mandatory. ISO alpha-2 code for participating countries. Mandatory. Mandatory. Mandatory. For SWEDEHEART this is the CENTERID that the User is logged in to while screening Mandatory. For SWEDEHEART this is the USERID for the current User

45 Screening (cont d) SUBJECT_ID ID of the Study Subject Text Only if the Patient was included in the Study. The corresponding entry is then present in the Subject Log REASON_NOT_INCLUDED REASON_NOT_INCLUDED_DETAIL Reason for not including the patient Detailed information about why the patient was not included [NO_INFORMED_CONSENT _REQUESTED, NO_INFORMED_CONSENT_POSSIBLE, NO_INFORMED_CONSENT_OBTAINED, DID_NOT_MEET_CRITERIA] [SYMPTOM_DURATION, NOT_HIGH_RISK_NSTEMI, PCI_NOT_PERFORMED, NOT_MVD, PREVIOUS_CABG LEFT_MAIN_DISEASE, CARDIOGENIC_SHOCK, OTHER] Only if the patient was not included. Only if the REASON_NOT_INCLUDED has value DID_NOT_MEET_CRITERIA

47 Summary Fast inclusion of large patient numbers Focus on hard endpoints Complete follow-up Fraction of costs Important complement to RCTs R-RCTs could potentially revolutionise clinical trials

48 Consequences Potential benefits for registries: Academic - increased impact as tool for knowledge discovery Administrative - increased funding Regulative - increased legitimacy Technological - increased integration Clinical - nuisance to necessity

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