Stefan James, Uppsala University 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

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

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 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%

Thrombus aspiration in Sweden SWEDE HEART SCAAR Thrombus aspiration in Sweden

/ Swedish registry data Fröbert, O. et al. Int J Cardiol. 2010; 145:572-3 HR (95% CI): 1.21 (1.08-1.35) / Swedish registry data PCI alone (N=16 417) TA+PCI (N=3 666) TAPAS Data 2005-2009 Vlaar, P.J. et al. The Lancet 2008; 371:1915-20

Obeservational studies (None-inverventional) 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

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

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 SWEDE HEART

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.

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

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.

Data entry on line by the operator 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 Angiographic background data

SWEDE HEART SWEDE HEART Name Name

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?

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

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

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

TASTE and previous studies

> 1000 patients > 100 patients Hospital Randomized Total STEMI Proportion randomized Lund PCI 1020 1591 64% Göteborg SU Sahlgr PCI 941 1500 63% Stockholm KS Solna PCI 463 1094 42% Örebro PCI 442 603 73% Uppsala PCI 413 602 69% Linköping PCI 337 723 47% Falun PCI 295 550 54% Gävle PCI 283 547 52% Karlstad PCI 280 489 57% Skövde PCI 246 475 Umeå PCI 265 462 Skejby PCI 247 419 59% Stockholm SöS PCI 228 390 58% Sunderbyn PCI 222 397 56% Jönköping PCI 206 521 40% Eskilstuna PCI 205 372 55% Landspitali PCI 156 333 Kalmar PCI 147 327 45% Karlskrona PCI 108 364 30% Helsingborg PCI 99 144 Stockholm Danderyd PCI 93 187 50% Trollhättan NU-sjukvården PCI 77 208 37% Halmstad PCI 73 176 41% Sundsvall PCI 72 145 Västerås PCI 130 Borås PCI 65 106 61% Malmö PCI 64 157 Stockholm KS Huddinge PCI 44 116 38% Kristianstad PCI 37 86 43% Stockholm St Göran PCI 35 84 Göteborg SU Östra PCI 7 19 > 1000 patients > 100 patients

TASTE trial 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=3621 were followed up N=3623 were followed up N=1162 were followed up N=3535 were followed up

All-cause mortality at 30 days HR 0.94 (0.72 - 1.22), P=0.63 Per protocol analysis based on actual treatment: HR 0.88 (0.66 - 1.17), P=0.38

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

Stent thrombosis Reinfarction 2.7 Lagerqvist NEJM 2014 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 0.61 (0.34 - 1.07), P=0.09 HR 30 days 0.47 (0.20 - 1.02), P=0.06 Lagerqvist NEJM 2014

Reinfarction up to 1 year 2.7 HR up to 1 year 0.97 (0.73 – 1.28), P=0.81 HR up to 30 days 0.61 (0.34 - 1.07), P=0.09

Stent thrombosis up to 1 year 0.7 0.9 HR up to 1 year 0.84 (0.50 – 1.40), P=0.51 HR up to 30 days 0.47 (0.20 - 1.02), P=0.06

Death, hospitalization for MI or stent thrombosis up to 1 year HR up to 1 year 0.94 (0.80 – 1.11), P=0.48 8.5% 8,0% 8.5% PCI 8,0% PCI+TA HR up to 30 days 0.86 (0.68 – 1.09), P=0.22

Approval of new pharmaceutical agents and medical devices 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

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)

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

Study design Simple hypotesis, one question- one answer Sub-studies limited and simple Treatment alternatives available Well defined randomized options Open lable with blinded evaluation of events (PROBE) Blind, placebo controlled? Vi stödjer också klinisk forskning genom att erbjuda våra tjänster inom området. Vi har arbetat länge inom området och har därför många erfarenheter som kan komma till nytta i nya projekt. Vi är flexibla och kan arbeta med korta uppdrag, såväl som uppdrag som spänner över flera år.

Study procedures Complete protocol Approved by agencies and authorities Risk based monitoring GCP – appy but don’t over shoot Source data verification Data safety and monitoring committee (DSMB) Vi stödjer också klinisk forskning genom att erbjuda våra tjänster inom området. Vi har arbetat länge inom området och har därför många erfarenheter som kan komma till nytta i nya projekt. Vi är flexibla och kan arbeta med korta uppdrag, såväl som uppdrag som spänner över flera år.

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

Safety – and additional variables Extra sampling, tests, -demands on patients, requirements from authorities The more safety data to collect the more similar to classical RCT Safety survaillance (AE, SAE, SUSAR)

Informed consent, IC According law and ethics approval Oral + written Monitor signed IC Elecronic?

Randomization Continuous on-line Registry identifies patients and propose randomization Few pre-randomization variables Look all pre randomization variables

Data quality High requirements for all registry variables Monitoring Accreditation Store study specific study variables in a separate data base Swedeheart (Riks-HIA, SCAAR (kranskärlsröntgen och kateterburen kranskärlsbehandling), SEPHIA (kranskärlssjukdom), Svenska hjärtkirurgiregistret) Delar av registret har funnits sedan nästan 20 år. N = 600 000 totalt vårdtillfällen totalt. Cirka 60 000 patienter registrerades årligen varav 20 000 är hjärtinfarkter.

Relevant registry variables Data base Clincial register (variabler ex. personual ID) Other national registries (PAR, LM, ) Study database Alla variabler Personal ID replaced to study coode Cannot be changed Analyse databas Personal ID replced with study code Relevant registry variables Extra study specific variables Informed consent Randomisation code Incl-/exclusion critera Swedeheart (Riks-HIA, SCAAR (kranskärlsröntgen och kateterburen kranskärlsbehandling), SEPHIA (kranskärlssjukdom), Svenska hjärtkirurgiregistret) Delar av registret har funnits sedan nästan 20 år. N = 600 000 totalt vårdtillfällen totalt. Cirka 60 000 patienter registrerades årligen varav 20 000 är hjärtinfarkter. Available Data checks All patients kept untial behålls tills ev återtaget samtycke 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

1:1 online randomisation Study design Eligible patient*: After informed consent 1:1 online randomisation in ambulance or ED Oxygen 6l/min for (6-)12h via Oxymask Air *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

Economy Stable realistic budget Fonds Industry SKL

Ongoing R-RCT VALIDATE (n=6000) DETOX-AMI (n=7000) 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.

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