1. 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

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

4. Level of Evidence A Current GuidelinesAF
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%

5. Thrombus aspiration in Sweden
SWEDE HEART
SCAAR
Thrombus aspiration in Sweden

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

7. 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

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

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
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 CCU hospitals, 100%
SCAAR 30 PCI hospitals, 100%
Percutaneous valves 7 hospitals, 100%
Heart surgery 7 hospitals, 100%
Secondary prevention hospitals, 85%
>200 variables
(Baseline data, procedural and outcome measures)
At monitoring: 95-96% agreement between files and registry.

13. 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

14. SWEDE HEART SWEDE HEART
Name
Name

15. 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?

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

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

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

19. TASTE and previous studies

20. > 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

21. TASTE trial enrollment flow chart
Enrolled in Denmark
N=247
All patients with STEMI in Sweden and Iceland undergoing
primary or rescue PCI. N= *)
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

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

23. 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 ( ), P=0.63

24. 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 ( ), P=0.09
HR 30 days 0.47 ( ), P=0.06
Lagerqvist NEJM 2014

25. 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 ( ), P=0.09

26. 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 ( ), P=0.06

27. 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

30. 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

31. 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)

32. 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

33. 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.

34. 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.

35. 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

36. 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)

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

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

39. 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 = totalt vårdtillfällen totalt. Cirka patienter registrerades årligen varav är hjärtinfarkter.

40. 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 = totalt vårdtillfällen totalt. Cirka patienter registrerades årligen varav 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

43. 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

44. Economy
Stable realistic budget
Fonds
Industry
SKL

45. 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.

46. 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