SWEDE HEART

1. Lessons from the TASTE trial Prospective Registry based Randomized Clinical Trials (R-RCT) – a new concept for clinical research Stefan James, Uppsala University Sweden SWEDE HEART

3. Which Treatment is Best for Whom?High-Quality Evidence is Scarce Tricoci P et al. JAMA 2009;301:831-41 3

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

5. SCAAR SWEDE HEART Thrombus aspirationin Sweden

6. TAPAS / Swedish registry data TA+PCI (N=3 666) PCI alone (N=16 417) HR (95% CI): 1.21 (1.08-1.35) Vlaar, P.J. et al. The Lancet 2008; 371:1915-20 Fröbert, O. et al. Int J Cardiol. 2010; 145:572-3

7. Register studies Obeservational studies (None-inverventional) Strengths • Ideal for description of standars • Unselected patient populations –generalizable • Large number of events – makes it possible to identify rare events • Inexpensive Weaknesses • Data quality variable and questionable • Cannot be used for comparative outcomes research • Confounding factors can not be adjusted for despite advanced statistical models

8. Randomized Controlled/Clinical Trials - RCT Non randomized Observational studies Randomized Studies (RCT)

9. Randomized Clinical Trials- RCT Weaknesses Strengths • Correctly designed studies with adequate power are gold standard • Extinguishes confounding • Highly selected populations due to exclusion criteria • Often selected specialized study centers • Often surrogate endpoints • Long time to plan and complete • Expensive • Often sponsored by industry- only studies with economic interest will be performed SWEDE HEART

10. Register based Randomized Clinical trials- R-RCT Is a prosective randomized trial but it uses a clinical registry for one or several major functions for trial conduct.

11. Registry based Randomized Clinical trials - R-RCT Strengths • Correctly designed studies with adequate power are gold standard • Extinguishes confounding • Unselected patient populations –generalizable • Large number of events – makes it possible to identify rare events • Inexpensive Weaknesses • Data quality lower • Variable definition

12. Number of cases annually: 80 000 RIKS-HIA 73 CCU hospitals, 100% SCAAR 30 PCI hospitals, 100% Percutaneous valves 7 hospitals, 100% Heart surgery 7 hospitals, 100% Secondary prevention 65 hospitals, 85% >200 variables (Baseline data, procedural and outcome measures) At monitoring: 95-96% agreement between files and registry.

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

14. 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 exclusioncrieteriamet?

15. Information for consent Did the patient consent? Are inclusion and exclusioncrieteriamet?

16. Randomize and store data Did the patient consent? Are inclusion and exclusioncrieteriamet?

17. TASTEinclusion rate Patients All primary PCI:s Randomized 7244 patients Date

18. TASTE and previous studies TASTE

19. TASTEtrial enrollment flow chart Enrolled in Denmark N=247 All patients with STEMI in Sweden and Iceland undergoing primary or rescue PCI. N=11 709 *) Enrolled in TASTE N=7259 • Not enrolled • N=4697 • Erroneous enrollments • N=15 Randomized in TASTE N=7244 No patients (0) were lost to follow-up of the primary outcome! 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=1162 were followed up N=3621 were followed up N=3623 were followed up N=3535 were followed up

20. All-cause mortality up to 1 year HR up to 1 year 0.94 (0.78 – 1.15), P=0.57 HR up to 30 days 0.94 (0.72 - 1.22), P=0.63

21. Reinfarction Stent thrombosis 2.7 2.7 HR 1 year 0.97 (0.73 – 1.28), P=0.81 HR 1 year 0.84 (0.50 – 1.40), P=0.51 HR 30 days 0.47 (0.20 - 1.02), P=0.06 HR 30 days 0.61 (0.34 - 1.07), P=0.09 Lagerqvist NEJM 2014

23. R-RCT vs. classical RCT • New concept for clinical research • Combines the advantages of a clinical registry and randomized study • Complement to classical RCT –No substitute • RRCT • Evaluation of therapeutic options available/used in routine clinical care RCT Approval of new pharmaceutical agents and medical devices

24. What can a registry do? • Identify patients • Randomize • Collect baseline and procedure characteristics (CRF) • Assist with and collect consent forms • Identify clinical endpoints (endpoint detection) • Control clinical outcome events (adjudication, CEC) Some or all parts of trial

25. Study design

26. Study design • Simple hypotesis, onequestion- oneanswer • Sub-studies limited and simple • Treatment alternatives available • Welldefinedrandomized options • Openlablewithblindedevaluationof events (PROBE) • Blind, placebo controlled?

27. Endpoints • Well defined, death optimal • Clinical • Complete • Available (Delay for Swedish hospital admission registry) • Central clinical event committee (CEC) is needed if not well defined events- particularly for open label trials

28. Data base Other national registries(PAR, LM, ) Clincial register (variabler ex. personual ID) Studydatabase Alla variabler Personal ID replacedtostudycoode Cannot be changed Analyse databas Personal ID replcedwithstudycode Relevant registryvariables Extra studyspecific variables Informedconsent RandomisationcodeIncl-/exclusioncritera Available Data checks All patients kept untial behålls tills ev återtaget samtycke Available for registrystaff/ PI Possibilitytoremove patients from registry Available for registry staff/ for registry staff/trialists Not possible to remove patients from a trial

29. Study design • *Inclusion criteria: • symptoms suggestive of AMI within 6h • SpO2 ≥ 90% • ≥ 30y • ECG changes indicating ischemia • and/or elevated troponin levels Primary Endpoint: 1-year total mortality Additional secondary endpoint and sub studies Data analysis through SWEDEHEART registry and national mortality registry

30. Ongoing 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.

31. Conclusions • Large need for randomized trials (RCT) particularly for the evaluation of strategies, devices, pharmacological therapies • Classical RCTs are often not performed in broad representative patient populations • The national clinical registries are strong networks for collaboration and enroll complete patient populations • Prospective Registry based Randomized Clinical Trials (RRCT) is a new opportunity for clinical research • RRCT is ideal for one clinically important hypothesis with reliable hard endpoints