Swedeheart registry RRCT: Randomiserade Register Studier. Bo Lagerqvist Akademiska sjukhuset Uppsala

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2 Swedeheart registry RRCT: Randomiserade Register Studier Bo Lagerqvist Akademiska sjukhuset Uppsala

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4 Which Treatment is Best for Whom? High-Quality Evidence is Scarce 4 Tricoci P et al. JAMA 2009;301:831-4

5 Level of Evidence A Current Guidelines AF Heart failure PAD STEMI Perioperative Secondary prevention Stable angina SV arrhythmias UA/NSTEMI Valvular disease VA/SCD PCI CABG Pacemaker Radionuclide imaging 0.3% 6.4% 6.1% 4.9% 4.8% 11.7% 15.3% 13.5% 12.0% 9.7% 11.0% 19.0% 22.9% 23.6% 26.4% 0% 10% 20% 30%

6 Randomized Clinical Trials- RCT SWEDE SCAAR HEART Strengths Correctly designed studies with adequate power are gold standard for comparative clinical trials Extinguishes confounding Weaknesses Expensive Long time to plan and complete Highly selected populations Often selected specialized study centers Often surrogate endpoints (Late lumen loss, TLR vs. Angina, MI) Often sponsored by industry- only studies with economic interest will be performed

7 Registerstudier av behandlingseffekter??

8 Kranskärl

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10 PCI Percutan Transluminal Intervention

11 Stent

12 Efter ballong Före behandling Stentat kärl

13 Swedish Coronary Angiography and Angioplasty Registry (SCAAR) Founded and managed by the profession Supported by the Swedish health authorities Independent of the Industry All 29 PCI centers contributes : PCI procedures Angiography only procedures

14 SWEDEHEART National coverage Hospitals No Patients Annual No RIKS-HIA coronary intensive care registry SCAAR (coronary angiography and PCI) 100 % % % % Thoracic surgery 100 % 8 100% 7000 SEPHIA Secondary Prevention After Myocardial Infarction(<75 yrs) 85% 65 55% 5500 TAVI 100 % % 150

15 History - SWEDEHEART Regional CCU registry 1989 Open heart surgery 1992 RIKS-HIA - National CCU registry 1995 SCAAR coronary angiography and PCI 1998 Internet platform - RIKS-HIA & SCAAR UCR National Registry Center 2002 SEPHIA secondary prevention, rehabilitation 2005 SWEDEHEART 2009 Heart 2010;96:

16 SWEDE HEART Name, personal ID number Data entry on line by the operator Administrative data Clinical background and prior CV disease Automatic linkage with population registry Automated data checks Angiographic background data

17 SCAAR Scientific presentations :

18 Other registries: NDR, SCB, Cancer, FK. SCAAR merging example of Events /Endpoints: From SCAAR: Complications New procedures (angio/pci) Restenosis Stent occlusions/stent thrombosis From other part of SWEDEHEART: Infarctions (STEMI NSEMI) From Registry of Population (merge every month): Death From Registry of death cause (every year, 1-2 yrs lag): Cause of death From Registry of diagnosis (every year, 1-2 yrs lag): Hospitalizations due to ICD (AMI, stroke, renal failure) Op codes ( CABG, dialysis ) From Prescribed Drug Register: Drug prescription since July 2005.

19 Svagheter Confounding factors ofta omöjliga att fullt kompensera för trots avancerad statistik Data kvalitén ofta sämre Missing values kan ge oönskad selektion Fodrar ofta avancerad statistik med multivarabel analys och propensity score, svårvärderat, svarta lådan effekten, risk för övervärdering. Styrkor Kliniskt viktiga endpoints sällan surrogat endpoints Stora studerade grupper tillåter analys av ovanliga händelser och endpoints Oselekterade populationer generaliserbara resultat till alla patienter Alla centers är med resultaten kan generaliseras till alla typer av sjukhus Billigare Snabbare Register studier

20 Randomiserade Studier (RCT) Icke randomiserade Observations studier

21 Randomiserade Studier (RCT) Icke randomiserade Observations studier

22 Rangordning av olika behandlingsstudier 1. Randomiserade studier 2. Metaanalys av randomiserade studier 3. Register studier men en bra registerstudie kan vara bättre än en dålig randomiserad studie 4. Metaanalys av register och randomiserade studier 5. Metaanalys av register studier

23 Registerstudier vs RCT Vid studier av behandlingseffekter är Randomiseringen kunskapens moder När det inte finns randomiserade studier eller när dessa är otillräckliga är registerstudier ett alternativ men måste då tolkas med försiktighet. Kan hjälpa till att utöka till grupper som är för små eller som är exkluderade ifrån randomiserade studier. ex2 ex3

24 Example 1 Restenoses after treatment of In-Stent Restenosis (ISR)? 7,806 ISR treated in Sweden Original stent: DES 2,629 BMS 5,177 Schwalm T. et al, Eurointervention 2013

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27 Example 1 Restenoses after treatment of In-Stent Restenosis (ISR)? 7,806 ISR treated in Sweden Original stent: DES 2,629 BMS 5,177 BMS DES Schwalm T. et al, Eurointervention 2013

28 SCAAR Results of different ISR-treatment SWEDE HEART Original stent -BMS DEB vs BMS 0.52 ( ) DES vs BMS 0.46 ( ) Schwalm T. et al, Eurointervention 2013

29 SCAAR Results of different ISR-treatment SWEDE HEART Original stent -BMS Original stent -DES DEB vs BMS 1.06 ( ) DEB vs BMS 0.52 ( ) DES vs BMS 0.99 ( ) DES vs BMS 0.46 ( ) Schwalm T. et al, Eurointervention 2013

30 Results of different ISR-treatment SWEDE SCAAR HEART Original stent -BMS Original stent -DES BMS vs POBA 1.34 ( ) DES vs POBA 0.80 ( ) DES vs POBA 0.62 ( ) Schwalm T. et al, Eurointervention 2013

31 In DES-ISR, does a change of desdrugs helps? SWEDE SCAAR HEART Schwalm T. et al, Eurointervention 2013

32 In DES-ISR, does a change of desdrugs helps? SWEDE SCAAR HEART Change vs Same drug 1.14 ( ) Schwalm T. et al, Eurointervention 2013

33 None, of these results are definite answers,. they have to be further evaluated in other clinical studies were the treatment selection is based on randomization, not on doctors choice

34 Sometimes is the difference between treatments so big that observational data can also early and in small materials can give strong signals.

35 Example 2 Comparison of restenosis rate with 2 different Drug-Eluting Balloons SCAAR April September ,236 patients treated with : Braun SeQuent Please N=919 Aachen Resonance ELUTAX, N=217 Bondesson P. et al, Eurointervention 2012

36 Example 2 Comparison of restenosis rate with 2 SCAAR different Drug-Eluting Balloons April September ,236 patients treated with : Braun SeQuent Please N=919 Aachen Resonance ELUTAX, N=217 SWEDE SCAAR HEART Bondesson P. et al, Eurointervention 2012

37 Example 2 Comparison of restenosis rate with 2 different Drug-Eluting Balloons SWEDE SCAAR HEART SCAAR April September ,236 patients treated with : Braun SeQuent Please N=919 Aachen Resonance ELUTAX, N=217 SeQuent vs ELUTAX, overall: Crude 0.42 ( ) Adjusted 0.39 ( ) Bondesson P. et al, Eurointervention 2012

38 Cumulative Rate of Restenosis (%) Reported Restenosis within 1 year in DEBs used April 2009-Sept e 2013 in Sweden Drug Eluting Balloons o Achen Braun Resonance Sequent ELUTAX Ple a N=2 933 N=348 Ivatec In.Pact Fa l N=247 Aachen Resonance Elutax N=308 Biotronik Pantera N=382 SWEDE SCAAR HEART Braun Sequent Please N=2,933 Ivatec In.Pact Falcon N=247 Biotronik Pantera Lux N= Time (Days after PCI with DEB) 360

39 Example 3 Reported stent thrombosis SWEDE SCAAR HEART Stents from 2007 Group Total BS Libertè Abbott Xience Prime BS Promus Element Medtronic Driver Medtronic Integrity BS Taxus Liberté Medtronic Resolute Integrity Abbott multilink Vision Other stents Cordis Cypher XienceV or Promus BS Omega Medtronic Endeavor Hexacath Titan2 Medtronic Endeavor Resolute Braun Coroflex Blue Abbott Multilink8 Sorin Chrono Biosensors BioMatrix Biotronik Orsiro Count Mean Std Deviation

40 Stent-thrombosis

41 Example 3 Reported stent thrombosis SWEDE SCAAR HEART

42 Example 3 Reported stent thrombosis SWEDE SCAAR HEART Adjusted

43 Example 3 Reported stent thrombosis SWEDE SCAAR HEART Can the differences in SAT risk be explained by The stent it self or by how the different stents are used???

44 In summary: The most important weakness of registry studies of treatment effect is that differences between the groups usually generates much bigger differences in measured effect than the real difference between the treatments!

45 Kan vi göra något åt detta??

46 Kan vi låta lotten avgöra exponeringen i en registerstudie. Där alternativen används kliniskt och är väl kända. Där skillnaderna avseende effekter och hantering är ganska små. Där vi kan använda otvetydiga outcomes.

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48 Trombaspiration

49 Bakgrund Trots primär PCI har ST elevations AMI fortfarande en hög 1 års mortalitet Trombaspiration förbättrar Incidens av stenttrombos TIMI flow grade Myocardial blush ST-segment resolution efter STEMI - och (därför) kanske också no reflow Ett antal randomiserade trombaspirationsstudier har visat vinst på surrogat endpoints En single center studie, TAPAS, med 1071 patienter, visade bättre överlevnad efter 1 år 49

50 TAPAS 4,6% 2,3%

51 SCAAR ESC guidelines SWEDE HEART Specific PCI devices and pharmacotherapy Joint 2010 ESC - EACTS Guidelines on Myocardial Revascularisation

52 Thrombus aspiration in Sweden SWEDE SCAAR HEART

53 Cumulative risk of death Registry Studies SWEDE SCAAR HEART 0,20 Thrombus aspiration in Sweden ,15 Yes (N=3 666) 0,10 No (N=16 417) 0,05 HR (95% CI): 1.21 ( ) 0, Years after PCI 4 5

54 TASTE trial enrollment flow chart Enrolled in Denmark N=247 All patients with STEMI in Sweden and Iceland undergoing primary or rescue PCI. N= * ) Erroneous enrollments N=15 Enrolled in TASTE N=7259 Randomized in TASTE N=7244 Not enrolled N=4697 N=3621 assigned to thrombus aspiration N=3623 assigned to conventional PCI N=3399 underwent thrombus aspiration N=222 underwent conventional PCI N=3445 underwent conventional PCI N=178 underwent thrombus aspiration N=1162 underwent thrombus aspiration N=3535 underwent conventional PCI N=3621 were followed up N=3623 were followed up N=1162 were followed up N=3535 were followed up

55 Two questions need to be answered: Did the patient consent orally? Are inclusion and no exclusion criteria met? Did the patient consent? Are inclusion and exclusion crieteria met?

56 Did the patient consent? Are inclusion and exclusion crieteria met? Information for consent

57 Did the patient consent? Are inclusion and exclusion crieteria met? Randomize and store data

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59 All-cause mortality up to 1 year HR up to 1 year 0.94 ( ), P=0.57 HR up to 30 days 0.94 ( ), P=0.63

60 Death, Hosp for MI or Stent thrombosis (%) 8 Death, hospitalization for MI or stent thrombosis up to 1 year 8.5% 8.5% PCI 8,0% 6 PCI+TA HR up to 1 year 0.94 ( ), P= HR up to 30 days 0.86 ( ), P= Months

61 Stent thrombosis up to 1 year HR up to 1 year 0.84 ( ), P=0.51 HR up to 30 days 0.47 ( ), P=0.06

62 TOTAL

63 R-RCT vs. Klassisk RCT Kombinerar fördelarna med register och RCT Komplement till klassisk RCT Ingen ersättning Flytande gräns mellan klassisk RCT och R-RCT R-RCT Värdering av strategier och behandlingar som redan används i klinisk rutin RCT Nya, oprövade läkemedel och tekniska hjälpmedel

64 Studietyp RCT R-RCT Strategi + Device CE märkt, använt + Device, first in man + Läkemedel i klinisk praxis + Läkemedel för ny indikation + + Nytt läkemedel + db

65 Studiedesign Enkel hypotes, en fråga-ett svar Sub-studier begränsade och enkla Behandlingsalternativen måste finnas i klinisk rutin Väl definierade randomiseringsalternativ Öppen med otvetydigt utfall Öppen med blind värdering av utfall Blind, placebokontrollerad db

66 Studieprocedurer Komplett protokoll Godkänd av nämnder och myndigheter Riskbaserad monitorering GCP ska följas men kan ofta göras enkelt Källdatakrav (Source data verification) Data säkerhets och monitoreringskommittee (DSMB) db

67 Utfallsmått (Endpoint) - Väl definierade, död enklast - Kliniska - Komplett - Tillgänglig (fördröjning i PAR) - Central händelseutvärdering (CEC) måste göras för händelser som kan tolkas olika-speciellt viktigt för öppna studier db

68 Säkerhets- och andra variabler Extra prover, undersökningar-krav på patienten, krav från myndgheter Ju mer säkerhetsdata desto mer likt traditionell RCT Safety survaillance (AE, SAE, SUSAR) db

69 Informerat samtycke - Enligt gällande lag och EPN godkännande - Muntligt + skriftligt - Signerade samtycken måste monitoreras - Elekroniska? db

70 Randomisering - Kontinuerlig on-line - Registret hittar patienter och föreslå randomisering - Få pre-randomiseringsvariabler - Lås alla pre randomiseringsvariabler db

71 Datakvalitet - Höga krav på alla registervariabler - Monitorering - Ackreditering - Behåll specifika studievariabler i separat databas db

72 Databas Kvalitetsregister (variabler ex. personnummer) Extra studiespecifika variabler Informed consent Randomiseringskod Incl-/exclusion kriterier Studiedatabas Alla variabler Personnummer ersätts med studiekod Kan inte ändras Andra nationella register (PAR, LM, ) Analysdatabas Personnummer ersätts med studiekod Relevanta registervariabler Tillgängligt för registerpersonal/prövare Möjlighet att avlägsna patienter från register Tillgängligt för registerpersonal/prövare Inte möjligt att avlägsna patienter från studie Tillgängligt för registerpersonal/prövare/ monitorer Data checks Alla patienter behålls tills ev återtaget samtycke

73 Planerade eller pågående R-RCT VALIDATE (n=6000) Bivalirudin versus Heparin in NST and ST- Elevation myocardial infarction in patients on modern antiplatelet therapy in SWEDEHEART, DETOX-AMI (n=7000) DETermination of the role of OXygen in Acute Myocardial Infarction, SWEDEPAD (n=2480) SWEdish Drug Elution trial in Peripheral Arterial Disease. DES vs BMS and DEB vs POBA. IFR SWEDEHEART (n=2000) Instantaneous Wave-Free Ratio versus Fractional Flow Reserve in ACS PROSPECT-2 (n=1200, hybrid trial) Providing Regional Observations to Study Predictors of Events in the Coronary Tree. Evaluate future events from cholesterol plaques detected by near infrared spectroscopi DISCO (n=2480) Evaluate if patients with out of hospital cardiac arrest should undergo routine coronary angiography U-CARE (n=500) Evaluation of internet based cognitive behavioural therapy (icbt) versus usual care in patients with depression/anxiety post MI.

74 Tack!

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