SWEDE HEART

Prospective Registry based Randomized Clinical Trials (R-RCT) –

a new concept for clinical research

Lessons from the TASTE trial

Stefan James, Uppsala University

Sweden

3 Tricoci P et al. JAMA 2009;301:831-41Tricoci P et al. JAMA 2009;301:831-41

Which Treatment is Best for Whom?High-Quality Evidence is Scarce

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%

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

SWEDE HEART

SCAARThrombus aspirationin Sweden

Vlaar, P.J. et al. The Lancet 2008; 371:1915-20

TAPAS

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)

Strengths

• Data quality variable and questionable

• Cannot be used for comparative outcomes research

• Confounding factors can not be adjusted for despite advanced

statistical models

• Ideal for description of standars

• Unselected patient populations –generalizable

• Large number of events – makes it possible to identify rare events

• Inexpensive

Weaknesses

Register studiesObeservational studies (None-inverventional)

RandomizedStudies (RCT)

Non randomizedObservational studies

Randomized Controlled/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

Randomized Clinical Trials- RCT

Is a prosective randomized trial but it uses a clinical registry for one or several major functions for trial conduct.

Register based Randomized Clinical trials- R-RCT

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

Automatic linkage with population registry

Automated data checksClinical background and prior CV disease

Angiographic background data

Administrative data

Name, personal ID number

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?

Randomized

All primary PCI:s

7244 patients

Date

Patients

TASTE inclusion rate

TASTE and previous studiesTASTE

All patients with STEMI in Sweden and Iceland undergoing

primary or rescue PCI. N=11 709 *)

Enrolled in TASTEN=7259

N=3621 assignedto thrombus aspiration

N=3399 underwentthrombus aspirationN=222 underwentconventional PCI

TASTE trial enrollment flow chart

Not enrolled N=4697

N=3623 assignedto conventional PCI

N=3535 underwent conventional PCI

N=1162 underwentthrombus aspiration

N=3445 underwentconventional PCIN=178 underwent

thrombus aspiration

N=3621 werefollowed up

N=3623 werefollowed up

N=1162 werefollowed up

N=3535 werefollowed up

Enrolled in DenmarkN=247

Erroneous enrollments

N=15

Randomized in TASTEN=7244

No patients (0) were lost to follow-up of the

primary outcome!

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

2.72.7

Reinfarction

HR 1 year 0.97 (0.73 – 1.28), P=0.81

HR 30 days 0.61 (0.34 - 1.07), P=0.09

Stent thrombosis

HR 1 year 0.84 (0.50 – 1.40), P=0.51

HR 30 days 0.47 (0.20 - 1.02), P=0.06

Lagerqvist NEJM 2014

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

RCTApproval of new

pharmaceutical agents and medical devices

R-RCT vs. classical RCT

• 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

What can a registry do?

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?

Study design

- 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

Endpoints

Data base

Informed consentRandomisation code

Incl-/exclusion critera

Extra study specificvariables

Clincial register (variabler ex. personual ID) Study database

Alla variabler

Personal ID replaced to study coode

Cannot be changed

Analyse databas

Personal ID replced with study code

Relevant registry variables

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

Available

Data checks

All patients kept untial behålls tills ev återtaget samtycke

Other national registries (PAR, LM, )

Study design

Primary Endpoint: 1-year total mortalityAdditional secondary endpoint and sub studies

Data analysis through SWEDEHEART registry and national mortality registry

*Inclusion criteria:• symptoms suggestive of AMI within 6h• SpO2 ≥ 90%• ≥ 30y• ECG changes indicating ischemiaand/or elevated troponin levels

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.

Ongoing R-RCT

• 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

• 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

Conclusions