National registries for quality improvement and research

Transcription

1 Swedish experiences: National registries for quality improvement and research Stefan James Professor of Cardiology Uppsala Clinical Research Centre Uppsala University Uppsala, Sweden

2 Evidence based health care development Clinical trials Diagnostic methods Basic research Guidelines- Scientific evidence Implementation Registers evaluation Real world evidence

3 Which Treatment is Best for Whom? High-Quality Evidence is Scarce < 15% of guideline recommendations supported by high quality evidence 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%

4 Conclusion Clinical trials registered in ClinicalTrials.gov are dominated by small trials and contain significant heterogeneity in methodological approaches, including reported 4 use of randomization, blinding, and DMCs. 4

5 "Unfortunately, too many of the decisions made today about health and healthcare are not supported by high quality evidence, Current clinical trials are too slow, too expensive, not reliable, and not designed to answer the important questions Rob Califf, Commissioner for medical products & tobacco FDA. Applied clinical trials.

6 Cost of doing trials

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8 Challenges and opportunities Enormous gap between evidence and need for evidence Costs are skyrocketing Technical development growing Clinical registries, digitalized health records, A new path is indicated- to facilitate better, faster, easier, and more cost effective clinical research 8

9 Beautiful but expensive and cumbersome Good enough Simple, inexpensive but inapproprate IKEA style Usual Clinical Trial after Regulatory/FDA/Academic Interactions Well planned and conducted pragmatic trial Poorly planned pragmatic trial

10 Data bases for baseline characteristics and outcomes in Sweden Since year month day place sex ctrl Public mandatory registries Outpatient diagnosis registry Sweden statistics Prescription registry Population registry Hospital admission registry ICD EHRs Hospitals and primary care

11 Data bases for baseline characteristics and outcomes in Sweden Since year month day place sex ctrl Outpatient diagnosis Quality Registries registry Sweden statistics Prescription registry Population registry Hospital admission registry ICD EHRs Hospitals and primary care

12 Sweden s 96 quality registries Knee prosthesis Hip prosthesis RiksHIA Coronary Care Diabetes Prostatecancer Swedeheart

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14 Thrombus aspiration SWEDE SCAAR HEART

15 Thrombus aspiration SWEDE SCAAR HEART

16 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

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

18 Register based Randomized Clinical trials- R-RCT Prosective randomized trial that uses a clinical registry for one or several major functions for trial conduct and outcomes reporting.

19 Study design

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

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

22 The simplest and most pragmatic design HR 1 year 0.94 ( ), P=0.57 HR up to 30 days 0.94 ( ), P=0.63

23 Registry based Patient Follow-up STEMI Thrombectomy Story Registry-based Follow-up Standard site-based Follow-up 500,000 15,000,000 1 st patient: June centers 33 months to full enrollment 1 st patient: August centers 48 months to full enrollment Fröbert et al. N Engl J Med 2013 Oct 24;369(17): Lagerqvist B et al. N Engl J Med 2014;371: Jolly SS et al. N Engl J Med 2015;372:

24 Guidelines Title Citation Class LOE 2012 ESC Guidelines STsegment elevation myocardial infarction. European Heart Journal 2012 Oct;33(20): Routine aspiration should be considered IIa B 2014 ESC/EACTS guidelines on myocardial revascularization Eur Heart J Oct 1;35(37): May be considered in selected patients IIb A 2015 ACC/AHA focused update PPCI JACC Routine thrombectomy not useful III A 2015 ACC/AHA focused update PPCI JACC Selective and bailout Thrombectomy not well established IIb C 2017 ESC Guidelines STsegment elevation myocardial infarction European Heart Journal 2017 Routine use of thrombus aspiration is not recommended. III A

25 Thrombus aspiration post Taste SWEDE HEART Mean use during trial Mean use immediately after trial

26 Eligible patient*: In ambulance, ED or cath lab N=6600 Oxygen 6l/min for (6-)12h via Oxymask R 1:1 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 Funding: Swedish Research council (VR)

27 Randomization in ambulance, ED, cath lab or CCU

28 Primary Endpoint up to 365 days Oxygen treatment Ambient air Ambient air 5.1 % Oxygen treatment 5.0 % HR % CI, P=0.8

29 Relief of hypoxaemia and symptoms Recommendations Clas s Lev el Hypoxia Oxygen is indicated in patients with hypoxaemia (SaO2 <90% or PaO2 <60 mmhg). I C NEW Routine oxygen is not recommended in patients with SaO2 90%. III B ESC Guidelines for the Management of AMI-STEMI (European Heart Journal doi: /eurheartj/ehx095)

30 VALIDATE (R-RCT) STEMI (n=3000) or NSTEMI (n=3000) Pre-treatment with Ticagrelor, Prasugrel or Cangrelor Angiography: PCI intended R 1:1 Heparin only (70-100U/kg) Bivalirudin (5000U Heparin pre-hospital or 3000U pre-pci) Primary Endpoint: NACE: Death, Myocardial Infarction or Bleeding complication (BARC 2, 3 or 5) at 6 months FU: Register data, combined with phone call endpoint follow up and CEC Funding: Heart-lung foundation. Swedish research council, Astra Zeneca, The Medicines company.

31 Included NSTEMI/STEMI in relation to possible eligible patients in Sweden 25 PCI centers out of 29 in Sweden participated in the trial 47.8% (6006 of 12,561) of all patients in Sweden presenting at enrolling hospitals with an initial diagnosis of STEMI or NSTEMI planned for PCI were randomized. All potential patients Enrolled Of all patients potentially eligible for enrollment, 70.0% (6006 of 8585) were randomized.

32 Primary Endpoint at 180 days HR % CI, P=0.54

33 Total n=4052 patients 2026 patients in each arm Exclude: Previous CABG Left main disease Cardiogenic chock Primary PCI of STEMI/rescue- PCI/risk evaluation following thrombolysis/very high risk NSTEMI > 1 non-culprit lesions Visual estimation non-culprit vessel at least 2.5 mm on angiography (50-99%) amenable for PCI 1:1 Randomization Within 6 h from puncture time of index procedure Eligible but not randomized FFR-guided PCI of non-culprit lesions during index admission* Initial conservative management of non-culprit lesions Registry follow-up Trial follow-up for endpoints at 30 days and at least 1 year *Admission meaning initial PCI-capable unit or after transfer to another PCI-capable unit

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35 SPIRRIT- HFPEF Patients enrolled from ~ eligible patients in registry N=3200 Spirinolactone R 1:1 The Swedish Heart Failure Registry (SwedeHF) Standard of care Stable chronic HF Age 50 years EF 40% NT-proBNP > 300 (sinus rhythm); > 750 (AF) Event driven 632 events Primary Endpoint: Cardiovascular death, Secondary efficacy endpoints: HF hospitalization and other cardiovascular outcomes Safety endpoints related to renal function and potassium Uppsala Clinical Research Center

36 Conventional vein harvesting Domingos Souza, Kärl-Thoraxkliniken, USÖ

37 No touch - techniqe Domingos Souza, Kärl-Thoraxkliniken, USÖ

38 SWEDEGRAFT A Nordic, multicenter, prospective, randomized, register based, clinical trial on notouch vein graft (NT-graft) in coronary surgery First time CABG Need for at least one vein graft N=700 R 1:1 Vein grafts harvested and implanted with the nontouch technique Vein grafts harvested and implanted with standard technique Primary Endpoint: Proportion of patients with graft failure defined as: SVGs occluded/stenosed >50% on CCTA or has undergone percutaneous intervention to a vein graft or died within two years after CABG. Secondary Endpoint: MACE, including all cause death, myocardial infarction and repeated revascularization Incidence of postoperative leg wound complications from the harvesting site. The frequency of non-significant vein graft stenosis (20-50%) Funding: Heart-lung foundation.

39 R-RCTs in Sweden (known to us) TASTE (n=7200) Thrombus aspiration in primary PCI Clinical registry: Swedeheart Funding: Swedish Heart-Lung foundation, Sw Research council, Medtronic, Vascular Solutions, Terumo. Study sponsor and ARO: ifr Swedeheart (n=2018) ifr vs FFR in stable angina or ACS Clinical registry: Swedeheart Funding: Volcano. Study sponsor and ARO: UCR. VALIDATE (n=6006) Bivalirudin vs UFH for PCI in ACS Clinical registry: Swedeheart Funding: Swedish Heart-Lung foundation, Sw Research council, The MedCo, AZ Study sponsor and ARO: UCR DETO2X (n=6629) Oxygen therapy in suspected myocardial infarction Clinical registry: Swedeheart Funding: Swedish Heart-Lung foundation, Sw Research council. Study sponsor: Karolinska Institute. ARO: UCR SLITS (n=2507) Closure of the meso-defect at gastric by pass operation Clinical registry: SOREG Funding: O rebro County Council, Stockholm City Council, and the Erling-Persson Family Foundation Sponsor: O rebro University SWEDEPAD (N=2400) Drug Elution trial in Peripheral Arterial Disease, Clinical registry: SwedVasc - Swedish vascular surgery registry Funding: Sw Research council. Study sponsor: Göteborg University. ARO: UCR TIMING (n=3000) Time point for NOAC treatment after ischemic stroke in atrial fibrillation Clinical registry: Swedish Stroke Registry Funding: Swedish Research council (VR), Study sponsor: UCR. ARO: UCR Completed Completed Completed Completed Completed Ongoing Ongoing

40 R-RCTs in Sweden (cont d) PROSPECT-2 (n=1200, hybrid trial) near infrared spectroscopi Clinical registry: Swedeheart Funding: The Medicines Company/ Abbot vascular. Study sponsor: UCR FULL-REVASC (n=4000) FFR-guidance for ST elevation myocardial infarction revascularization Clinical registry: Swedeheart Funding: Swedish Research council (VR), Study sponsor: Karolinska Institute. ARO: UCR SWEPIS (n=10 000) Post-term Induction of labour Clinical registry: Pregnancy Register and Swedish Neonatal Q registry Study sponsor: Göteborg University IAMI (n=4400) Influenza vaccination After Myocardial Infarction Clinical registry: Swedeheart Funding: Sanofi, Study sponsor: O rebro University hospital. ARO: KTC BEST (N=4000) Gastric by pass vs sleeve operation in obesity surgery Clinical registry: SOREG Study sponsor: Göteborg University SPIRRIT HFpEF (n=3200) Spironolactone for HFpEF Clinical registry: SwedeHF Funding: Swedish Heart and lung foundation. NIH, Erling Persson Study sponsor: UCR. ARO: UCR Ongoing Ongoing Ongoing Ongoing Ongoing Ongoing

41 R-RCTs in Sweden (cont d) REDUCE (n=6600) Betablocker post MI in patients with normal left ventricular function. Funding: Swedish Research council (VR), Study sponsor: Karolinska Institute. ARO: UCR Swedegraft (n=800) Patency of vein grafts for CABG surgery evaluated by coronary CT Clinical registry: Swedeheart Funding: Swedish Heart and lung foundation. Study sponsor: UCR. ARO: UCR MINOCA BAT (n=2048) ACE/ARBi after MI with non-obstructive coronary arteries Clinical registry: Swedeheart Funding: Swedish Research council (VR). Study sponsor: UCR. ARO: UCR TACSI (n=2048) Ticagrelor and ASA vs. ASA alone after CABG in patients with ACS Planned Clinical registry: Heart surgery/ Swedeheart Funding: Swedish Research council (VR). Study sponsor: Göteborg University. ARO: UCR ABC AF (n=6500) ABC-risk score based treatment strategies in patients with AF Clinical registry: AURICULA Funding: Swedish Foundation for Strategic Research, Sw Heart-Lung Foundation, Roche Diagnostics. Study sponsor: UCR Ongoing Soon to start Soon to start Planned

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44 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)

45 R-RCT vs. classical RCT 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

46 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 + +

47 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?

48 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)

49 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

50 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)

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

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

53 Data quality - High requirements for all registry variables - Monitoring - Accreditation - Store study specific study variables in a separate data base

54 Data base Clincial register (variables ex. personal ID) Extra study specific variables Informed consent Randomisation code Incl-/exclusion critera Study database All variables Personal ID replaced with study code Variables locked Other national public registries Analyze databas Open registry data base Variables can be changed Possible to remove patients from registry Not possible to remove patients from a trial Variables locked Cleen file Data base lock