Registerbaserade randomiserade kliniska pro vningar Innovativa exempel fra n dagens pa ga ende hja rt- forskning i Sverige

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1 Registerbaserade randomiserade kliniska pro vningar Innovativa exempel fra n dagens pa ga ende hja rt- forskning i Sverige SWEDE HEART Stefan James, Professor Kardiologi Vetenskaplig ledeare UCR, Uppsala

2 Klinisk forskning i KRIS

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

4 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%

5 Thrombus aspiration in Sweden SWEDE SCAAR HEART

6 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

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 Randomized Studies (RCT) Non randomized Observational studies

9 Randomized Clinical Trials- RCT Strengths Correctly designed studies with adequate power are gold standard Extinguishes confounding Weaknesses 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

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 Data quality lower Variable definition Weaknesses

12 Number of cases annually: RIKS-HIA 73 CCU hospitals, 100% SCAAR 30 PCI hospitals, 100% Percutaneous valves7 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 Clinical background and prior CV disease Automatic linkage with population registry Automated data checks Angiographic background 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 exclusion crieteria met?

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

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

17 TASTE inclusion rate Patients All primary PCI:s Randomized 7244 patients Date

18 TASTE and previous studies TASTE TAPAS JETSTENT AIMI INFUSE-AMI VAMPIRE PREPARE Chevalier Kaltoft MUSTELA X AMINE ST PIHRATE EXPIRA DEAR-MI Liistro Number of patients

19 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=3621 were followed up N=3445 underwent conventional PCI N=178 underwent thrombus aspiration N=3623 were followed up N=1162 underwent thrombus aspiration N=1162 were followed up N=3535 underwent conventional PCI N=3535 were followed up

20 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

21 Reinfarction Stent thrombosis HR 1 year 0.97 ( ), P=0.81 HR 1 year 0.84 ( ), P=0.51 HR 30 days 0.61 ( ), P=0.09 HR 30 days 0.47 ( ), P=0.06

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23 Use of thrombus aspiration post Taste Mean use during trial

24 COCHRANE review 2010 There is NO evidence from randomised controlled trials to support the routine use of inhaled oxygen in patients with acute myocardial infarction. A definitive randomised controlled trial is urgently required given the mismatch between trial evidence suggestive of possible harm from routine oxygen use and recommendeations for its use in clinical practice guidelines. The Cochrane Library 2010:6.:CD007160

25 Eligible patient*: After informed consent 1:1 online randomisation in ambulance or ED *Inclusion criteria: symptoms suggestive of AMI within 6h SpO2 90% 30y ECG changes indicating ischemia and/or elevated troponin levels Oxygen Air 6l/min for (6-)12h via Oxymask Primary Endpoint: 1-year total mortality Additional secondary endpoint and sub studies Data analysis through SWEDEHEART registry and national mortality registry

26 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 No strict definition or limitation Methodology and plat form depend on the hypothesis, outcome and setting RRCT Evaluation of therapeutic options available/used in routine clinical care RCT Approval of new pharmaceutical agents and medical devices

27 What can a registry do? Some or all parts of trial 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)

28 STEMI or NSTEMI Treatment with ticagrelor or prasugrel pre-pci Bivalirudin (Heparin max 5000U) Heparin only (according to local PM) Primary endpoint: Death, MI, Major bleeding at 6 months. Follow up 1, 2, 3, 5 and 10 years.

29 VALIDATE-RRCT A substudy to prove the validity of pharmaceutical RRCTs, by comparing with a phone follow up, monitored, adjudicated RCT Randomised in VALIDATE Short inclusion CRF Phone call 7d Phone Call 6 months Final comparison in VALIDATE-RRCT SWEDEHEART register follow up

30 Study design RCT R-RCT Strategy + Device CE mark, used + Device, first in man + Approved drugs used in clinical practise Drugs for new indication + + New drugs + +

31 Data base Clincial register (variabler ex. personual ID) Extra study specific variables Informed consent Randomisation code Incl-/exclusion critera Study database All variables Personal ID replaced to study coode Cannot be changed Other national registries (PAR, LM, ) Analyse databas Personal ID replced with study code Relevant registry variables Available Available for registry staff/ PI Possibility to remove patients from registry Available for registry staff/ for registry staff/trialists Not possible to remove patients from a trial Data checks All patients kept untial behålls tills ev återtaget samtycke

32 Ongoing R-RCT in Sweden 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=900, 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.

33 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