Registries for clinical research - rcso.sercso.se/wp-content/uploads/2016/11/Stefan-James-Om-att-använda-kv... · All patients with STEMI in Sweden and Iceland undergoing primary

Registries for clinical research

Stefan James Professor of Cardiology Uppsala Clinical Research Centre Uppsala University Uppsala, Sweden

The anatomy of the Swedish personal iden4fica4on number

640429-‐6730 year month day place sex ctrl

Quality Registries

EHRs Hospitals and primary care

Sweden statistics Prescription registry

Data bases for baseline characteristics and outcomes in Sweden

Hospital admission registry

ICD

Population registry

Outpatient diagnosis registry

A selection of mandatory Swedish national registries

Olika typer av kvalitetsregister •  ”Interventionsregister”, ex höftledsop

•  ”Diagnos - vårdepisodsregister”, ex hjärtinfarkt

•  ”Diagnos – långtidsregister”, ex diabetes

Kvalitetsregister vid UCR

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 67 hospitals, 85%

Cardio genetics 5 university hospitals

Cardiac CT 10 large hospitals

Continuous bio banking 3 university hospitals

>300 variables (Baseline data, procedural and outcome measures)

At monitoring: 95-96% agreement between files and registry.

Keys for success

• Simple registration process

• The users are highly motivated • The users have direct use of the system-

to print study reports and stats

• SCAAR is not just a registry - provides clinical information.

• Flexibility, the users can influence the contents and create own variables

• Merging with other registries

SWEDE HEART

Data entry on line by the operator

Automatic linkage with population registry to provide name, sex

Automated data checks

Clinical background and prior CV disease

Angiographic background data

Administrative data

Name, personal ID number

Refered from

Date of procedure Type of registration

Office /call service Local hospital

Body length

Body length (cm)

S-creatinine (ug/L

Creatinine clearance (ml/min) Prior PCI Prior CABG

Diabetes Smoking

Auto populated fields from previous registrations

Calculated variables

History is presented and all previously implanted stents have to be checked

Learning health care systems

RR: 1.03 (0.84,1.26)

0.0 0.5 1.0 1.5 2.0 2.5 3.0

0.00

0.02

0.04

0.06

0.08

0.10

Time (years)

Cum

ulat

ive ri

sk o

f dea

th

RR: 1.32 (1.11,1.57)

BMS 12880 12473 12354 12228 9298 5966 3199DES 5770 5605 5541 5471 3434 1777 626

RR 1.3 (1.1-1.6)

Future potential increased mortality?

??

5 y

Patients enrolled 2003-2004 and followed max 3 years

N=19 771

N Engl J Med 2007;356:1009-19.

BMS vs DMS Bare metal stents vs. Death metal stents

“The SCAAR registry is contaminated with flaw data….” M Leon 2007

The SCAAR Scare

“This clearly shows how inappropriate registry studies are….” Kastrati 2007

“What is rotten in the kingdom of Sweden” P. Serruys 2008

Years after PCI

Cum

ulat

ive

rate

of d

efin

ite s

tent

thro

mbo

sis

(%)

2 1 0

2

1

0.5 0.5% early

0

1.5

N=64 979 stents

Unadjusted BMS, N=38 649

Slope 0.5% per year

DES, N=26 330

Lagerqvist, Circ Cardvasc Int 2009 Oc;2(5):401-8

Stent thrombosis SCAAR SWEDE HEART

SCAAR

0 1 2 3 4 5

0.00

0.05

0.10

0.15

Time (years)

Cumu

lative

risk of

death

BMSDES

BMS 28286 26843 19429 13592 6682 7DES 19681 18893 12691 6065 1964 0

RR: 0.82 (0.73, 0.92)

RR: 1.06 (0.97, 1.17)

Patients enrolled 2003-2006 and followed max 5 years

N= 47.867

James, N Engl J Med 2009;360(19):1933-45

New generation DES n-DES vs o-DES: adjusted HR 0.62; 95% CI: 0.53-0.72 n-DES vs BMS: adjusted HR: 0.29; 95% CI: 0.25-0.33 o-DES vs BMS: adjusted HR: 0.46; 95% CI: 0.43-0.51

BMS o-DES n-DES

Adjusted

Sarno et al ESC 2011

n-DES vs o-DES: adjusted HR: 0.50; 95% CI: 0.35-0.71 n-DES vs BMS: adjusted HR: 0.33; 95% CI: 0.23-0.47 o-DES vs BMS: adjusted HR: 0.65; 95% CI: 0.54-0.46

BMS o-DES n-DES Adjusted

n-DES vs o-DES: adjusted HR: 0.77; 95% CI: 0.63-0.95 n-DES vs BMS: adjusted HR: 0.55; 95% CI: 0.46-0.67 o-DES vs BMS: adjusted HR: 0.72; 95% CI: 0.64-0.81

BMS; N=42773 o-DES; N=12153 n-DES; N= 6425

Adjusted

New DES 0.7%

BMS 1.7%

Old DES 2.9%

All stents implanted 2005- September 2016 N= 304 367

Crude rates

Example Comparison of restenosis rate with 2 different Drug-Eluting Balloons

� SCAAR

� April 2009- September 2011 1,236 patients treated with :

–  Braun SeQuent® Please N=919

–  Aachen Resonance ELUTAX® , N=217

SWEDE HEART

SCAAR

Crude 0.42 (0.26-0.68) Adjusted 0.39 (0.24-0.65)

Bondesson P. et al, Eurointervention 2012;8(4):444-9

Time (Days after PCI with DEB)

360270180900

Cumulative Rate of Restenosis (%)

14

12

10

8

6

4

2

0

Reported Restenosis within 1 year in DEBs used April 2009-Septe2013 in Sweden

Biotronik Pantera N=382

Aachen Resonance Elutax N=308

Ivatec In.Pact FalN=247

Braun Sequent PleaN=2 933

Drug Eluting BaloDrug Eluting Balloons

Braun Sequent PleaseN=2,933

Ivatec In.Pact FalconN=247Biotronik Pantera LuxN=247

Achen Resonance ELUTAXN=348

SWEDE HEART

SCAAR

back

* Comment

*The risk of Stent trombosis is based on the Kaplan Meier Estimat. For the Ultimaster stent only 9 stent thromboses was reported in 1156 stents. Eight of these in one hospital.

All stents 2007- Oct. 1, 2015 Adjusted N=83 334

Cumulative risk of stent thrombosis in individual stent types beyond 1 year

2.6 years

Jernberg JAMA. 2011;305(16):1677-1684

Mortality after ST- elevation MI

Comparative effectiveness

Comparative effectiveness

SWEDE HEART

SCAAR Thrombus aspiration

SWEDE HEART

SCAAR Thrombus aspiration

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)

Randomized Studies (RCT)

Non randomized Observational 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

Randomized Clinical Trials- RCT

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 studies Observational studies (Non-inverventional)

Prosective randomized trial that uses a clinical registry for one or several major functions for trial conduct and outcomes reporting.

Register based Randomized Clinical trials- R-RCT

�  Iden>fy pa>ents � Randomize

� Collect baseline and procedure characteris>cs (CRF) � Assist with and collect consent forms

�  Iden>fy clinical endpoints (endpoint detec>on) � Control clinical outcome events (adjudica>on, CEC)

Some or all parts of trial

What can a registry do?

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

Challenges

•  Data quality •  Variable definition

§  Combines the advantages of a clinical registry and randomized study

§  Complement to classical RCT –No substitute

§  No formal definition

� RRCT

� Evaluation of therapeutic options available/used in

routine clinical care

RCT Approval of new

pharmaceutical agents and medical devices

R-RCT vs. classical RCT

RCT R-RCT

Strategy +

Device – CE mark, used +

Drugs approved/ used in clinical practise

+

Drugs for new indication + +

Device, first in man +

New drugs +

Study design

Data base

Informed consent

Randomisation code Incl-/exclusion critera

Extra study specific Variables/ EDC

Clinical registry (variables incl.

personal ID) Study database

All variables

Personal ID Cannot be changed

Analyse database

Personal ID replaced with study code

Only relevant registry

variables

•  Open database •  Available for

investigators •  Possibility to remove

patients from registry

•  Available for registry staff/ for registry staff/trialists

•  Not possible to remove patients from a trial

•  Audit trail

Available for trialists, sponsor Data checks All patients

Other national registries (hospital discharge, pharmacy,

other clinical regsitries etc)

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


Randomize and store data


Randomized

All primary PCI:s

7244 patients

Date

Patients

TASTE inclusion rate

All patients with STEMI in Sweden and Iceland undergoing primary or rescue PCI. N=11 709 *)

Enrolled in TASTE N=7259

N=3621 assigned to thrombus aspiration

N=3399 underwent thrombus aspiration N=222 underwent conventional PCI

TASTE trial enrollment flow chart

Not enrolled N=4697

N=3623 assigned to conventional PCI

N=3535 underwent conventional PCI

N=1162 underwent thrombus aspiration

N=3445 underwent conventional PCI N=178 underwent

thrombus aspiration

N=3621 were followed up




Enrolled in Denmark N=247

Erroneous enrollments

N=15

Randomized in TASTE N=7244

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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

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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

Claims-based Patient Follow-up STEMI Thrombectomy Story

Claims-based Follow-up

Lagerqvist B et al. N Engl J Med 2014;371:1111-1120 Jolly SS et al. N Engl J Med 2015;372:1389-1398

1st patient: June 2010 30 centers 33 months to full enrollment 7,244 patients

1st patient: August 2010 87 centers 48 months to full enrollment 10,732 patients

Site-based Follow-up

500,000 € 15,000,000 €

Same composite clinical endpoint at 180 days

Claims-based Follow-up

Lagerqvist B et al. N Engl J Med 2014;371:1111-1120 Jolly SS et al. N Engl J Med 2015;372:1389-1398

Site-based Follow-up

CV

dea

th, M

I, S

hock

, HF

Thrombus aspiration post Taste

Mean use during trial

SWEDE HEART

Title Citation Class LOE

2012 ESC Guidelines ST-segment elevation myocardial infarction .

European Heart Journal 2012 Oct;33(20):2569-619

Routine aspiration should be considered

IIA B

2014 ESC/EACTS guidelines on myocardial revascularization

Eur Heart J. 2014 Oct 1;35(37):2541-619

May be considered in selected patients

IIB A

2015 ACC/AHA focused update PPCI

JACC on line Routine thrombectomy not useful

III A

2015 ACC/AHA focused update PPCI

JACC on line Selective and bailout Thrombectomy not well established

IIb C

Guidelines

Eligible patient*:

in ambulance, ED or cath lab

N=6600

Oxygen 6l/min for (6-)12h

via Oxymask

Air

Primary Endpoint: 1-year total mortality Additional 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 ischemia and/or elevated troponin levels

R 1:1

Funding: Swedish Research council (VR)

Randomization in ambulance, ED, cath lab or CCU

Inklud

erad

e pa

tienter

0

1000

2000

3000

4000

5000

6000

Datum

2013-‐01-‐01 2013-‐07-‐01 2014-‐01-‐01 2014-‐07-‐01 2015-‐01-‐01 2015-‐07-‐01 2016-‐01-‐01

Alla vårdenheterE nköping Detox-‐AMIGävle Detox-‐AMIGöteborg S U Mölndal Detox-‐AMIGöteborg S U S ahlgr Detox-‐AMIGöteborg S U Östra Detox-‐AMIHalmstad Detox-‐AMIJ önköping Detox-‐AMIK almar Detox-‐AMIK arls tad Detox-‐AMIK iruna Detox-‐AMIK ris tianstad Detox-‐AMIK öping Detox-‐AMIL idköping Detox-‐AMIL indesberg Detox-‐AMIL inköping Detox-‐AMIL jungby DE TOX -‐AMINorrköping Detox-‐AMINorrtälje Detox-‐AMINyköping DE TOX -‐AMIS kövde Detox-‐AMIS tockholm Danderyd Detox-‐AMIS tockholm K S Huddinge Detox-‐AMIS tockholm K S S olna Detox-‐AMIS tockholm S t Göran Detox-‐AMIS tockholm S öS Detox-‐AMIS undsvall Detox-‐AMIS US L und Detox-‐AMIS US Malmö Detox-‐AMITrelleborg DE TOX -‐AMIUmeå Detox-‐AMIUppsala Detox-‐AMIVarberg Detox-‐AMIVäxjö Detox-‐AMIÖrebro Detox-‐AMIÖrnsköldsvik Detox-‐AMI

35 hospitals

Total:

6650 enrolled

72% AMI Of these 55% STEMI

VALIDATE (R-RCT)

�  Hybrid R-RCT: Register data, register randomisation combined with phone call endpoint follow up and CEC

�  Funding: Heart-lung foundation. Astra Zeneca, The Medicines company.

�  Total cost: <2 million dollar

STEMI (n=3000) or NSTEMI (n=3000) Pre-treatment with Ticagrelor, Prasugrel or

Cangrelor Angiography: PCI intended

Primary Endpoint: NACE: Death, Myocardial Infarction or Bleeding

complication (BARC 2, 3 or 5) at 6 months

Heparin only (70-100U/kg)

Bivalirudin (5000U Heparin pre-hospital

or 3000U pre-PCI)

R 1:1

Randomisation Module

•  Register identifies eligible patients

•  Asks the operator if patient agrees to participate

•  If yes, immediate randomisation result

•  Performed in a few seconds

Randomisation results

Included NSTEMI/STEMI in relation to possible eligible patients in Sweden

Eligible

Enrolled

>60% of all eligible patients in a whole country is enrolled

Randomised in VALIDATE

Inclusion CRF

7 days CRF

SW

ED

EH

EA

RT

regi

ster

follo

w u

p

Study data base

1500 and 3000 patients DSMB

Comparison of 6 months endpoint data

Phone Call 6 months

CRF

A substudy to prove the validity of pharmaceutical R-RCT, by comparing a Hybrid R-RCT (phone follow up, CEC) with a pure R-RCT

Background data from SCAAR

VALIDATE R-RCT

SPIRRIT- HFPEF

Patients enrolled from ~11.018 eligible patients in registry

N=3583

Primary Endpoint: All cause death, Secondary efficacy endpoints: HF hospitalization and other cardiovascular outcomes Safety endpoints related to renal function and potassium

Spirinolactone

Standard of care

R 1:1

• Stable chronic HF • Age ≥ 50 years • EF ≥ 40% • NT-proBNP

> 300 (sinus rhythm); > 750 (AF)

Event driven 1073 events

IFR SWEDEHEART (n=2000) Completed enrollment Instantaneous Wave-Free Ratio versus Fractional Flow Reserve in ACS Clinical registry: Swedeheart Funding: Volcano. Study sponsor: UCR

R-RCT Sweden

PROSPECT-2 (n=1200, hybrid trial) ongoing Providing Regional Observations to Study Predictors of Events in the Coronary Tree. Evaluate future events from cholesterol plaques detected by near infrared spectroscopi Clinical registry: Swedeheart Funding: The Medicines Company/ Abbot vascular. Study sponsor: UCR DISCO (n=2480) ongoing Evaluate if patients with out of hospital cardiac arrest should undergo routine coronary angiography Clinical registry: Swedeheart, Swedish Cardiac arrest registry Funding: Swedish Research council (VR). Study sponsor: UCR

U-CARE (n=500) ongoing Evaluation of internet based cognitive behavioural therapy (iCBT) versus usual care in patients with depression/anxiety post MI. Clinical registry: Swedeheart Funding: Swedish Research council (VR). Study sponsor: UCR

R-RCT in Sweden SOREG (n=2500) ongoing Closure of the meso-defect occuring at gastric by pass operation will reduce prostoperative ileus without increase in early severe complications

IAMI (n=4400) ongoing Influenza vaccination After Myocardial Infarction (IAMI trial) Clinical registry: Swedeheart Funding: Sanofi, Study sponsor: Örebro University hospital

TIMING (n=3000) soon to start enrollment Evaluation of efficacy and safety of the time point for treatment with NOAK after ischemic stroke and AF Clinical registry: Swedish Stroke Registry Funding: Swedish Research council (VR), Study sponsor: UCR

FULL-REVASC (n=4000) soon to start enrollment Ffr-gUidance for st eLevation myocardial infarction REVASCularization Clinical registry: Swedeheart Funding: Swedish Research council (VR), Study sponsor: Karolinska Institute

R-RCT in Sweden

Swedegraft (n=800) planned Patency of vein grafts for CABG surgery evaluated by coronary CT. Clinical registry: Swedeheart Funding: Swedish Research council (VR??). Study sponsor: UCR

REDUCE (n=6600) planned Betablocker post MI in patients with normal left ventricular function. Funding: Swedish Research council (VR??), Study sponsor: Karolinska Institute

Documents

Registries for clinical research - rcso.sercso.se/wp-content/uploads/2016/11/Stefan-James-Om-att-använda-kv... · All patients with STEMI in Sweden and Iceland undergoing primary