PERSPECTIVES

OPINION to protect patients and to ensure quality,

impede conduct of simple and important
Registry-based randomized clinical trials because of the economic barriers
required to overcome them.6,7 A catch22
trialsa new clinical trial paradigm situation might, therefore, exist in which
to protect the patients interests, evidence
Stefan James, Sunil V. Rao and Christopher B. Granger of effectiveness of common treatments is
never established.8 Ironically, patients are
Abstract | Randomized clinical trials provide the foundation of clinical evidence to routinely treated in practice with thera-
guide physicians in their selection of treatment options. Importantly, randomization is pies that have not been verified for efficacy
the only reliable method to control for confounding factors when comparing treatment and safety, and for which they have not
groups. However, randomized trials have limitations, including the increasingly provided consent. Therefore, novel ways
prohibitive costs of conducting adequately powered studies. Local and national to use existing data-collection platforms,
regulatory requirements, delays in approval, and unnecessary trial processes have such as qu ality-improvement registries,
led to increased costs and decreased efficiency. Another limitation is that clinical administrative claims, and electronic health
trials involve selected patients who are treated according to protocols that might not records, can provide an opportunity to
represent real-world practice. A possible solution is registry-based randomized clinical enhance patient enrolment in large, simple
trials. By including a randomization module in a large inclusive clinical registry with trials. Patients can then be randomly allo-
cated with most of their required baseline
unselected consecutive enrolment, the advantages of a prospective randomized trial
medical history already recorded, minimiz-
can be combined with the strengths of a large-scale all-comers clinical registry. We
ing the need for additional data collection
believe that prospective registry-based randomized clinical trials are a powerful tool for
and onsite monitoring. This concept is the
conducting studies efficiently and cost-effectively. foundation for the design of registry-based
James, S. etal. Nat. Rev. Cardiol. advance online publication 17 March 2015; doi:10.1038/nrcadio.2015.33 randomized trials, which we believe are a
powerful tool to increase the efficiency and
cost-effectiveness of clinical trials.
Introduction of pharmaceutical agents, medical devices,
The highest level of scientific clinical evi- and clinical procedures are being tested in Observational studies
dence stems from prospective, randomized, appropriately designed prospective rand- Large-scale clinical registries initiated to
controlled clinical trials, which control for omized trials. However, only a minority of assess the quality of clinical performance
confounding factors by establishing two the recommendations given in international are, at present, successfully collecting data
groups of patients who have balanced base- guidelines are based on the highest level of from consecutive patients in many hospitals
line characteristics. When well designed and evidence from prospective randomized and health-care organizations; Denmark,
performed, these trials are the gold standard trials.3 In addition, many trials are limited Sweden, and the UK have some of the most
for comparative studies. Nonrandomized, by the specific recruitment of patients complete national databases.9 Observational
underpowered, or single-centre randomized using narrow inclusion criteria and multi- studies from these large-scale registries or
trials, unsupported by other independ- ple exclusion criteria, thereby limiting the from trial databases provide valuable infor-
ent evidence, are generally not considered trials generalizability to real-world patients mation and enhance clinical guidance for
to be adequate to support a conclusion of seen in practice settings. 4 Drugs and diseases in which prospective randomized
efficacy.1,2 International guideline commit- medical devices are, therefore, frequently trials are missing or difficult to conduct
tees require more than one adequate and used outside of their approved indication.5 (Box 1). 10 The early detection of stent
well-controlled trial supporting a treat- Furthermore, large-scale randomized thrombosis and high mortality with the
ment to recommend that therapy with the clinical trials are complex and expensive first generation of drug-eluting stents and
highest level of evidence, which reflects to perform, and economic revenue is typi- the early evaluation of drug-eluting bal-
the need for independent verification of cally the primary incentive to initiate such loons within the SCAAR registry are exam-
experimentalresults.1,2 trials.6 Funding from government and other ples of important large observations.11,12
In medicine, and particularly within the sources for large trials to address many of Retrospective analyses of prospectively
field of cardiology, an increasing number the important clinical strategies, therapies, collected data are ideally used for descrip-
and medical devices that require evalua- tive studies to assess treatment patterns and
tion is limited. Consequently, many trials evaluate outcomes associated with therapies
Competing interests are too small to provide reliable estimates applied in clinical practice. These analyses
S.J. has received institutional research grants of the riskbenefit balance. Furthermore, might also provide complementary data
from Medtronic, Terumo, and Vascular Solutions
for the conduct of the TASTE trial. The other the regulatory and ethical requirements to those from randomized trials.13 Ideally,
authors declare no competing interests. for randomized clinical trials, developed with complete nonselective enrolment, a

NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 1

2015 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES
Box 1 | Main features of trials
Observational studies
Observational studies, drawn from large
populations, are complementary to
prospective randomized trials
Despite appropriate statistical
adjustments, some confounding factors
cannot be completely eliminated
The interpretation of observational
studies assessing treatment effects
must be approached with caution
Results should be considered
nondefinitive and hypothesis generating
Registry-based randomized clinical trials
Randomly assigning patients in a clinical
quality registry combines the features
of a prospective randomized trial with a
large-scale clinical registry
Registry-based trials are less selective
and enable fast enrolment, control of
nonenrolled patients, and the possibility
of very long-term follow-up
Inexpensive and simple designs are
the main strengths of registry-based
randomized clinical trials
The clinical registry can be used to
identify patients for enrolment, perform
randomization, collect baseline variables,
and detect end points
large-scale registry will truly reflect the
overall patient population, particularly if
the registry is integrated into the health-
care system. However, observational studies
have limited value for assessing differences
in therapeutic options owing to selection
bias and confounding factors, both meas-
ured (for which adjustment is possible) and
unmeasured (for which adjustment is not
possible). Observational studies are, there-
fore, not sufficiently reliable to estimate
modest treatment effects, and should not
be used for this purpose. For many treat-
ments, including ones that are commonly
used, randomized trials are highly unlikely
to be performed owing to complex study
procedures, small patient populations, lack
of funding opportunities for academia, or
lack of financial incentives for industry. For
these patient subsets, results from observa-
tional studies might be the only data avail-
able to evaluate safety and efficacy.14 For
the same reasons, many prospective rand-
omized trials are not adequately powered for
important clinical end points, and surrogate
end points that have not been sufficiently
validated are often used. An observational
study might also provide important data for
reliable power calculations that are needed
to achieve clinically meaningful results,
particularly in low-risk populations and in
trials to evaluate low-frequency events.
2 | ADVANCE ONLINE PUBLICATION
Registry-based randomized trials
A prospective trial requires several impor-
tant elements to be successful, includ-
ing the identification of eligible patients,
attainment of patient consent, random
assignment of treatment, collection of
baseline variables, and the detection and
adjudication of clinical end points (Box2).
A clinical registry can be used for some,
and ideally most, of these aspects. A reg-
istry can be used for collection of baseline
variables andto identify eligible patients for
the trial,and by using interactive methodol-
ogy, can also actively propose enrolment in
a trial. By incorporating randomization in a
clinical quality registry, some of the critical
attributes of a prospective randomized trial
can be combined with the practical features
of a large-scale clinical registry including
the main strengths of minimally-selected
consecutive enrolment and automated and
efficient patient identification and follow-
up (Table1).15,16 We describe such a pro-
spective randomized trial built on a registry
platform as a prospective registry-based
randomized clinical trial (RRCT).
An RRCT can efficiently and effectively
be used to assess hard clinical end points in
large patient cohorts, and is well suited for
open-label evaluation of commonly used
therapeutic alternatives in settings with
existing registries. A simple trial design
with open-label randomization, limited
monitoring of trial processes, data focused
on key outcomes, and no centralized event
adjudication is inexpensive, but has limi-
tations and is not suitable for all types of
trials. For drugs or medical devices that
require comprehensive safety reporting
or intense pharmacokinetic or pharmaco-
dynamic modelling, or trials that require
strictly defined end points, a traditional
trial methodology including blinding of
treatment alternatives, dedicated follow-up,
systematic monitoring, and formal adjudi-
cation is needed to ensure patient safety and
sufficient quality of end point reporting.
However, the linking of numerous func-
tionalities to a clinical registry might still be
possible. To date, RRCTs are being used to
evaluate treatments, strategies, and devices
or acute-phase pharmacological agents, but
no strict limit exists as to what therapy can
be evaluated with the registry link, as long as
patient safety is assured and existing regula-
tions are followed. RRCTs with efficient and
streamlined trial conduct might also be used
for the evaluation of pharmaceutical agents
for new indications. Depending on the trial
hypotheses, outcome variables, and specific
2015 Macmillan Publishers Limited. All rights reserved
aims, the registry can be used for most of
the typical trial functionalities or for collec-
tion of baseline variables only. Benefits of
the linkage to a registry might include the
capacity to identify patients, to enrol larger
proportions of patients, and to conduct
long-term follow-up at low cost. Another
important strength of an RRCT is the capac-
ity to describe and follow up the complete
reference population, that is, all patients
who are eligible but nonrandomized, as well
as noneligible individuals.
Low-cost, streamlined design
Conducting prospective randomized trials
can be tedious and expensive. Conse
quently, owing to both cost and the regu-
latory burden, many new and existing
interventions are not evaluated, and the
trials that are conducted are smaller and
less informative than they might other-
wise be. The RRCT design solves some of
these cost issues. A large reduction in cost
can be achieved by using existing hospital
and registry networks. The TASTE trial17,18
involved 7,400 patients and was performed
and completed with >90% cost saving com-
pared with similar randomized trials with
a conventional design. Internet-based plat-
forms, current systems for patient identifi-
cation, baseline and study data collection,
and event detection can all be used from
existing databases rather than arranging
and rebuilding electronic records and other
infrastructures for every new trial. Other
cost-saving aspects of an RRCT include
the limited number of trial-specific patient
visits and fewer problems with patient
retention. Furthermore, cost can be reduced
with the use of existing collaboration net-
works for site selection, web-based start-up
meetings, and focused risk-based moni-
toring of critical variables, excluding only
those variables that do not affect the main
outcome of the trial. However, a RRCT
should still be based on appropriate power
calculations to enrol enough patients and
acquire sufficient outcome events to dem-
onstrate effectiveness. The link to a registry
Box 2 | Collection of outcome variables
Detection of outcomes can be performed
by a registry or a separate method such
as telephone calls or outpatient visits
Short-term and long-term all-cause
mortality is a reliable hard end point that
does not require definition and has low
susceptibility to ascertainment bias
Outcome variables can be adjudicated if
subject to uncertainty
www.nature.com/nrcardio

can facilitate an accurate estimation of event
rates, and the event rate of the enrolled and
nonenrolled patients can be followed up to
place the trial population in the context of
an unselected population.
The TASTE experience
The RRCT concept was first implemented
within the SWEDEHEART registry, 9 in
which manual thrombus aspiration was pro-
spectively evaluated as an adjunctive treat-
ment to primary percutaneous coronary
intervention (PCI) for acute myocardial
infarction, with mortality as the primary
end point.17 The TASTE trial18 was a multi-
centre, prospective, randomized, controlled,
open-label clinical trial involving patients
with ST-segment elevation myocardial
infarction (STEMI) undergoing PCI. The
national comprehensive SWEDEHEART
registry 9,19 was used for all aspects of the
TASTE trial. The registry contains data for
all consecutive patients from all coronary
intervention centres in Sweden and Iceland.
SWEDEHEART is funded solely by national
health authorities and provides immedi-
ate and continuous feedback on processes
and quality-of-care measures. Baseline and
procedural data are entered into the reg-
istry directly online. Validation of source
data against electronic health records has
an overall agreement of 95%.9,19
The online registry was used to identify
patients suitable for inclusion in TASTE by
confirming that the patients were >18years
of age, that PCI was planned because of
STEMI, and that they had not previously
been included in the trial. The treating cli-
nician had to confirm only a few inclusion
criteria, such as correspondence between
an electrocardiogram finding and stenosed
artery, and obtain verbal consent from the
patient. The ethics committee requested a
written confirmation of the consent from
the patient as soon as possible after the pro-
cedure. Patients were randomly assigned
treatment directly in the registry clini-
cal report form, and no additional study-
related activities for staff or patients were
included in the study. All end points were
automatically collected from national regis-
tries. No study-specific monitoring of data
or event adjudication was performed during
the trial. Consequently, all-cause mortality
collected from the national population reg-
istry was chosen as the primary end point
of the TASTE trial. Secondary end points
such as stent thrombosis, repeat myocar-
dial infarction, stroke, and readmission
to hospital for heart failure were collected
NATURE REVIEWS | CARDIOLOGY ADVANCE ONLINE PUBLICATION | 3
PERSPECTIVES
Table1 | Advantages and disadvantages of different clinical trial designs
Clinical trial design Advantages Disadvantages
Registry studies and Ideal for description of standards Data quality is variable and questionable
observational studies Unselected patient populations Cannot be used for comparative
(generalizable cohorts) outcomes research
Large number of events allows Confounding factors cannot be adjusted
for the identification of rare for, despite advanced statistical models
events
Inexpensive
Randomized clinical Well-designed studies with Highly selected populations owing to
trials adequate power (gold-standard specific inclusion and exclusion criteria
clinical design) Often performed at specialized study
Removes confounding factors centres
Often include surrogate end points
Requires long time to plan and complete
Expensive
Often sponsored by industry (only studies
with economic interest will be performed)
Registry-based Randomization removes potential Data quality might be variable and
randomized clinical confounding questionable
trials Less-selected patient populations Variables might not be well-defined
Large number of events allows for Limited possibility for collection of detailed
the identification of rare events safety reporting, biospecimens, and
Simple design pharmacokinetics or pharmacodynamic
Inexpensive indices
from the SCAAR/SWEDEHEART registry random allocation of patients using a postal
and from the mandatory national hospital or interactive voice randomization system.
admission registry. In the SORTOUT studies, data was col-
In total, 7,244 patients were randomly lected in a specific clinical report form, but
assigned in the study.20 During 2years and national registries were used to detect clini-
9months of enrolment, 61% of all patients cal events such as death, myocardial infarc-
who presented with STEMI and were tion, and revascularization.21,22 Detected
referred for PCI, and 82% of all patients who events were thereafter adjudicated with
were potentially eligible for enrolment in standard methodology. This trial design
Sweden and Iceland were randomly assigned has two important advantages: the ability to
to receive either thrombus aspiration as an describe baseline demographics and clinical
adjunct to PCI, or PCI alone (Figure1). outcomes in all patients treated during the
Patients who were not randomly assigned study period, and not only those included
included those unable to give informed in the randomized controlled trial; and
verbal consent and, therefore, did not fulfil systematic end-point detection through
the inclusion criteria. No patients were lost registries without additional patient visits.
to follow-up for the primary end point owing A registry-based trial methodology was
to automated, personalized identification also used in the SAFEPCI for Women trial
number tracking. The trial showed no sig- in the USA, which incorporated a rand-
nificant difference in the primary end point omized trial into the existing cardiovascular
of all-cause mortality at 30days or at 1year.18 research infrastructure of the NIH National
While the cost of such a trial is subsidized Cardiovascular Data Registry CathPCI
by the existing registry and willingness of Registry.23 SAFEPCI for Women24,25 was a
investigators to participate for minimal prospective, randomized trial to compare
monetary compensation, the additional cost radial and femoral artery access in women
involved in establishing and administering undergoing PCI. The primary efficacy end
the SCAAR/SWEDEHEART registries was point was a composite of bleeding or vascu-
~US$400,000, compared with tens of mil- lar complication requiring intervention. The
lions of dollars for a study of equivalent trial design had two major advantages over
size using a traditional industryfunded traditional methodologies: using a clinical
trialmodel.18 registry for identification of trial sites and
investigators, and providing trialdata. The
Other registry-based trials registry enabled the identification of opera-
A number of stent trials performed by inves- tors and sites that could include patients
tigators in the Danish research network whose risk of femoral bleeding or vascu-
(the SORTOUT trials) have involved the lar complications was balanced by a risk
2015 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES

14,000 1year all-cause mortality from the Swedish

All primary PCIs
Population Registry was chosen as the
12,000 Randomly allocated in trial
primary end point. The estimated completion
of enrolment in this study is early 2016.
10,000
Finally, the VALIDATE-SWEDEHEART
trial28 is an open-label, multicentre, prospec-
8,000
Patients

tive, RRCT involving patients with myocar-

dial infarction and undergoing PCI. The trial
6,000
aim is to determine whether bivalirudin is
4,000
superior to heparin alone in reducing death,
n = 7,244
myocardial infarction, and major bleeding
2,000 61% of all patients events in patients with STEMI or NSTEMI,
82% of all eligible patients pretreated with ticagrelor or prasugrel, and
0 undergoing PCI. Investigators will enrol
3,000 patients with STEMI and 3,000 patients
J e

O mb t

O mb t
No cto er
Devember
Ja mb r
Fe nuaer

Apch
M il
ne

em st
NoOct ber
Devember
Ja mb r
Fe nuaer

Apch
M il
ne

No cto er
Devember
Ja mb r
Fe nuaer

ch
Se Au uly

br r y
M ar y

Ju y
Se Au July

br r y
M ar y

Ju ay

pt gu y

br r y
M ar y
e s

e s
ce be

ce be

ce be
a

Se A Jul
r

r
n

pt gu

pt gu
ar

ar

ar
Ju

with NSTEMI undergoing PCI. VALIDATE-

u

u
o

u
2010 2011
Figure 1 | Inclusion rate in the TASTE trial.18 All primary PCI procedures in Sweden between June
2010 and March 2013 are displayed in blue, and patients enrolled in the TASTE trial in red, during
the enrolment period of 2.5 years. Abbreviations: PCI, percutaneous coronary intervention.
of procedural failure with radial access, or
those at risk of vascular complications from
both radial and femoral approaches. Patient
demographics, medical history, concomi-
tant medications, procedural details, and
index hospitalization clinical outcomes are
routinely coded into the CathPCI regis-
trydata collection form using standardized
data elements and electronically captured
without the involvement of the study site
coordinator. For the SAFEPCI for Women
trial itself, extra information specific to
vascular access and bleeding definitions
that were not in the CathPCI Registry was
obtained using additional electronic case
report form pages.24 Overall, this approach
reduced the site coordinator workload by
~65% per patient, compared with the tra-
ditional study clinical report forms.25 The
resulting SAFEPCI database was designed
to be compliant with regulatory require-
ments for investigational new drug or device
exemption studies. The trial was successful,
but the cost savings was far less than that
in the TASTE trial, owing to the lack of full
integration of this registry into clinical care
and necessary redundancies.
The DETO2XAMI trial26 is the first RRCT
to assess the efficacy of a pharmacological
strategy using the SWEDEHEART registry
as a basis for randomization, baseline vari-
able collection, and primary outcome detec-
tion. Investigators in this trial are evaluating
whether supplemental oxygen, as compared
with normal room air, can reduce all-cause
mortality in 6,600 patients with suspected
or confirmed myocardial infarction. Patient
2012 2013
Date
Nature Reviews | Cardiology
randomization is performed in ambulances,
emergency departments, coronary care units,
and catheterization laboratories, by means of
an easily accessible online randomization
module in which a 10digit patient personal
identification number is entered. Inclusion
criteria, such as symptoms indicating myo-
cardial infarction, oxygen saturation >90%,
age >30years, and clinically significant
electrocardiogram changes or elevated tro-
ponin levels, and exclusion criteria such
as cardiac arrest before inclusion, need for
ambulatory continuous oxygen therapy,
and inability to consent, need to be con-
firmed before a patient is allocated to one
of the treatment alternatives. The randomi-
zation module automatically connects with
the SWEDEHEART registry for collection
of name and sex, and all data are automati-
cally transferred to the registry. All relevant
trial data are obtained directly from the reg-
istry with no other documentation needed.
Mortality data obtained outside the hospital
is collected by merging with the Swedish
Population Registry,27 which includes infor-
mation of the vital status of all Swedish
citizens. Merging with additional public
registries, including the National Patient
Registry, which contains information on
hospital discharge, allows for the collection
of other clinical end point data. However, a
trial design that uses national registries as
the only basis for follow-up is limited by the
lack of formal central adjudication of clini-
cal events. The DETO2XAMI trial26 also
has a potential for ascertainment bias, owing
to its open-label design. Consequently,
SWEDEHEART will use a hybrid RRCT
design, whereby randomization is per-
formed and baseline data are collected from
the SWEDEHEART registry.28 Clinical end
point data are collected through national
registries and phone calls after 7days and
180days, and adjudicated by a blinded
central end-point committee. Long-term
outcomes will also be accumulated from
later events recorded in the registry or in
public databases. The estimated completion
of enrolment is early 2016. RRCTs are cur-
rently promoted by the National Institutes of
Health6 and the Patient-Centered Outcomes
Research Institute in the USA as priorities to
address public-health needs.6,29
Conclusions
Study randomization controls for confound-
ing baseline differences and is an important
feature for studies designed to compare treat-
ment effect. By including a randomization
module in a large, all-inclusive clinical regis-
try with unselected consecutive enrolment,
some of the most important features of a pro-
spective randomized trial can be combined
with the inclusiveness and efficiencies of a
large-scale all-comers clinical registry. Such
trials can be described as a prospective RRCT
and are a powerful and highly cost-effective
tool to establish clinical evidence in many
areas of medicine that might not otherwise
be appropriately evaluated. The integration
of clinical trials and real-world practice is
critical to determine which treatments will
improve public health efficiently.
Uppsala Clinical Research Center, Uppsala
University Hospital, Dag Hammarskjlds vg
14B, 75237 Uppsala, Sweden (S.J.). The Duke
Clinical Research Institute, Duke University
Medical Center, 2301 Erwin Road, Durham,
NC27710, USA (S.V.R., C.B.G.).
Correspondence to: S.J.
stefan.james@ucr.uu.se

4 | ADVANCE ONLINE PUBLICATION www.nature.com/nrcardio

2015 Macmillan Publishers Limited. All rights reserved

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Author contributions
All the authors researched data for the article,
substantially contributed to discussion of content,
wrote, and reviewed and edited the manuscript
before submission.