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Thrombus Aspiration during ST-Segment Elevation Myocardial Infarction.
Fröbert, Ole; Lagerqvist, Bo; Olivecrona, Göran; Omerovic, Elmir; Gudnason, Thorarinn;
Maeng, Michael; Aasa, Mikael; Angerås, Oskar; Calais, Fredrik; Danielewicz, Mikael; Erlinge,
David; Hellsten, Lars; Jensen, Ulf; Johansson, Agneta C; Kåregren, Amra; Nilsson, Johan;
Robertson, Lotta; Sandhall, Lennart; Sjögren, Iwar; Ostlund, Ollie; Harnek, Jan; James,
Stefan K
Published in:
New England Journal of Medicine
DOI:
10.1056/NEJMoa1308789
2013
Link to publication
Citation for published version (APA):
Fröbert, O., Lagerqvist, B., Olivecrona, G., Omerovic, E., Gudnason, T., Maeng, M., Aasa, M., Angerås, O.,
Calais, F., Danielewicz, M., Erlinge, D., Hellsten, L., Jensen, U., Johansson, A. C., Kåregren, A., Nilsson, J.,
Robertson, L., Sandhall, L., Sjögren, I., ... James, S. K. (2013). Thrombus Aspiration during ST-Segment
Elevation Myocardial Infarction.
New England Journal of Medicine
,
369
(17), 1587-1597.
https://doi.org/10.1056/NEJMoa1308789
Total number of authors:
22
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n engl j med 369;17 nejm.org october 24, 2013
1587
The new england
journal of medicine
established in 1812
october 24, 2013
vol. 369 no. 17
Thrombus Aspiration during ST-Segment Elevation
Myocardial Infarction
Ole Fröbert, M.D., Ph.D., Bo Lagerqvist, M.D., Ph.D., Göran K. Olivecrona, M.D., Ph.D., Elmir Omerovic, M.D., Ph.D.,
Thorarinn Gudnason, M.D., Ph.D., Michael Maeng, M.D., Ph.D., Mikael Aasa, M.D., Ph.D., Oskar Angerås, M.D.,
Fredrik Calais, M.D., Mikael Danielewicz, M.D., David Erlinge, M.D., Ph.D., Lars Hellsten, M.D.,
Ulf Jensen, M.D., Ph.D., Agneta C. Johansson, M.D., Amra Kåregren, M.D., Johan Nilsson, M.D., Ph.D.,
Lotta Robertson, M.D., Lennart Sandhall, M.D., Iwar Sjögren, M.D., Ollie Östlund, Ph.D.,
Jan Harnek, M.D., Ph.D., and Stefan K. James, M.D., Ph.D.
ABSTRACT
From the Department of Cardiology, Öre-
bro University Hospital, Örebro (O.F.,
F.C.), Department of Medical Sciences,
Cardiology, and Uppsala Clinical Research
Center, Uppsala University, Uppsala (B.L.,
O.O., S.K.J.), Department of Cardiology,
Lund University Hospital, Lund (G.K.O.,
D.E., J.H.), Department of Cardiology,
Sahlgrenska University Hospital, Gothen
-
burg (E.O., O.A.), Department of Cardiol-
ogy, Karolinska Institutet, Sodersjukhuset
(M.A.), and Cardiology Unit, Department
of Medicine, Karolinska University Hospi
-
tal (U.J.), Stockholm, Department of Car-
diology, Karlstad Hospital, Karlstad (M.D.),
Department of Cardiology, Gävle Hospi
-
tal, Gävle (L.H.), PCI Unit, Sunderby Hos-
pital, Sunderby (A.C.J.), Department of
Cardiology, Västerås Hospital, Västerås
(A.K.), Department of Cardiology, Heart
Center, Umea University, Umea (J.N.),
Department of Cardiology, Borås Hospi
-
tal, Borås (L.R.), Department of Radiolo-
gy, Helsingborg Hospital, Helsingborg
(L.S.), and Department of Cardiology, Fa
-
lun Hospital, Falun (I.S.) — all in Sweden;
Department of Cardiology and Cardiovas
-
cular Research Center, Landspitali Univer-
sity Hospital of Iceland, Reykjavik, Iceland
(T.G.); and Department of Cardiology, Aar
-
hus University Hospital, Skejby, Aarhus,
Denmark (M.M.). Address reprint requests
to Dr. Fröbert at the Department of Cardi
-
ology, Örebro University Hospital, Södra
Grev Rosengatan, 701 85 Örebro, Sweden,
or at ole.frobert@orebroll.se.
This article was published on September 1,
2013, at NEJM.org.
N Engl J Med 2013;369:1587-97.
DOI: 10.1056/NEJMoa1308789
Copyright © 2013 Massachusetts Medical Society.
Background
The clinical effect of routine intracoronary thrombus aspiration before primary per-
cutaneous coronary intervention (PCI) in patients with ST-segment elevation myo-
cardial infarction (STEMI) is uncertain. We aimed to evaluate whether thrombus
aspiration reduces mortality.
Methods
We conducted a multicenter, prospective, randomized, controlled, open-label clini-
cal trial, with enrollment of patients from the national comprehensive Swedish
Coronary Angiography and Angioplasty Registry (SCAAR) and end points evaluated
through national registries. A total of 7244 patients with STEMI undergoing PCI were
randomly assigned to manual thrombus aspiration followed by PCI or to PCI only.
The primary end point was all-cause mortality at 30 days.
Results
No patients were lost to follow-up. Death from any cause occurred in 2.8% of the
patients in the thrombus-aspiration group (103 of 3621), as compared with 3.0% in
the PCI-only group (110 of 3623) (hazard ratio, 0.94; 95% confidence interval [CI],
0.72 to 1.22; P = 0.63). The rates of hospitalization for recurrent myocardial infarc-
tion at 30 days were 0.5% and 0.9% in the two groups, respectively (hazard ratio,
0.61; 95% CI, 0.34 to 1.07; P = 0.09), and the rates of stent thrombosis were 0.2%
and 0.5%, respectively (hazard ratio, 0.47; 95% CI, 0.20 to 1.02; P = 0.06). There were
no significant differences between the groups with respect to the rate of stroke or
neurologic complications at the time of discharge (P = 0.87). The results were con-
sistent across all major prespecified subgroups, including subgroups defined ac-
cording to thrombus burden and coronary flow before PCI.
Conclusions
Routine thrombus aspiration before PCI as compared with PCI alone did not reduce
30-day mortality among patients with STEMI. (Funded by the Swedish Research
Council and others; ClinicalTrials.gov number, NCT01093404.)
The New England Journal of Medicine
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The
new england journal
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n engl j med 369;17 nejm.org october 24, 2013
1588
O
ne of the most important thera-
peutic challenges in the management of
ST-segment elevation myocardial infarc-
tion (STEMI) is the establishment of normal cor-
onary blood flow after percutaneous coronary
intervention (PCI). Reduced flow is closely asso-
ciated with reperfusion injury,
1
which can lead to
arrhythmias, contractile dysfunction, microvas-
cular impairment, and irreversible myocardial
damage.
2
Reduced myocardial perfusion is also
associated with heart failure and death.
3,4
Coronary-artery thrombus aspiration, a sim-
ple, rapidly performed, and relatively inexpensive
adjunct to PCI, may improve blood flow and reso-
lution of ST-segment elevation,
5-9
although this
is not a universal finding.
10-12
Previous studies
of thrombus aspiration have not generally been
powered for hard clinical end points. The Throm-
bus Aspiration during Percutaneous Coronary In-
tervention in Acute Myocardial Infarction Study
(TAPAS), a single-center trial involving 1071 pa-
tients, in which mortality was a secondary end
point, suggested a survival benefit with throm-
bus aspiration among patients with STEMI.
6,13
However, coronary thrombus aspiration may come
at a price; a recent meta-analysis pointed to an
increased risk of stroke.
14
We conducted a randomized clinical trial to
evaluate the effect of thrombus aspiration on hard
clinical end points in patients with STEMI. To
make this investigator-initiated undertaking ec-
onomically and administratively feasible, we used
national registries as online platforms for random-
ization, case-record forms, and follow-up data,
thus conducting a registry-based randomized clin-
ical trial.
15
Methods
Study Design
The Thrombus Aspiration in ST-Elevation Myo-
cardial Infarction in Scandinavia (TASTE) trial
was a multicenter, prospective, open-label, ran-
domized, controlled clinical trial that used the
infrastructure of a population-based registry to
facilitate patient enrollment and data collection.
The trial design, which has been reported previ-
ously,
15
was approved by the regional ethics re-
view board in Uppsala, Sweden. Trial administra-
tion, data management, and statistical analyses
were performed at the Uppsala Clinical Research
Center at Uppsala University Hospital. The study
was designed and conducted by the authors, who
wrote all drafts of the manuscript and made the
decision to submit the manuscript for publication
(see the Supplementary Appendix, available with
the full text of this article at NEJM.org, for de-
tails). All the authors vouch for the integrity and
completeness of the data and analyses and for
the fidelity of this report to the trial protocol,
which is available at NEJM.org. None of the spon-
sors had access to the study data or had any role
in the design or implementation of the study or
the reporting of the data.
Patient Population
We enrolled trial participants from the national
comprehensive Swedish Coronary Angiography
and Angioplasty Registry (SCAAR), which is part
of the Internet-based Swedish Web System for En-
hancement and Development of Evidence-based
Care in Heart Disease Evaluated According to
Recommended Therapies (SWEDEHEART) regis-
try
16
(see the Supplementary Appendix for details).
This registry holds data on consecutive patients
from all 29 Swedish and 1 Icelandic coronary in-
tervention centers, is funded solely by national
health authorities, and provides immediate and
continuous feedback on processes and quality-
of-care measures. All baseline and procedural
data are entered online, directly into the registry.
For this study, an additional participating center
in Denmark entered all relevant data into SCAAR.
The data were monitored and adjudicated as part
of the regular registry validation; we did not per-
form separate, dedicated monitoring and adjudi-
cation of the data for the TASTE trial.
We considered for inclusion in the trial pa-
tients with STEMI for whom PCI was planned
after coronary angiography. Patients were eligi-
ble for the study if they had chest pain sugges-
tive of myocardial ischemia for at least 30 min-
utes before hospital admission, if the time from
the onset of symptoms to hospital admission
was less than 24 hours, and if an electrocardio-
gram (ECG) showed new ST-segment elevation
or left bundle-branch block (see the Supple-
mentary Appendix for details). Exclusion criteria
were the need for emergency coronary-artery
bypass grafting, an inability to provide informed
consent, an age younger than 18 years, and pre-
vious randomization in the TASTE trial.
After providing initial oral consent, patients
who fulfilled all inclusion criteria and had no
exclusion criteria were randomly assigned, in a
1:1 ratio, to thrombus aspiration followed by PCI
The New England Journal of Medicine
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Thrombus Aspiration during STEMI
n engl j med 369;17 nejm.org october 24, 2013
1589
or to PCI only. Randomization was performed by
means of an online randomization module with-
in the SCAAR database. All patients were asked
to confirm their agreement to participate by pro-
viding written informed consent within 24 hours.
Invasive Procedures
All the patients underwent coronary angiography
and PCI; the use of platelet inhibitors or antico-
agulants was left to the discretion of the treating
physician. For patients randomly assigned to
thrombus aspiration, guidewire placement was
followed by thrombus aspiration with the use of
a manual aspiration catheter before the PCI pro-
cedure (see the Supplementary Appendix for de-
tails). For both study groups, intracoronary ad-
ministration of nitrates after the restoration of
antegrade flow was recommended. Stenting was
encouraged, with the type of stent left to the dis-
cretion of the physician and with optional postdi-
lation (dilation of the stent after implantation).
The administration of P2Y
12
inhibitors was left to
the discretion of the physician; however, lifelong
treatment with acetylsalicylic acid was recom-
mended. Crossover from one group to the other
was discouraged, but if it did occur, it was re-
corded in the registry and the patient continued
to be followed up.
Trial End Points
The primary end point was all-cause mortality at
30 days, with data on mortality obtained from
the national population registry. The secondary
end points, for which data were obtained from
the SWEDEHEART registry and the national dis-
charge registry, included 30-day rates of hospi-
talization for recurrent myocardial infarction, stent
thrombosis, target-vessel revascularization, tar-
get-lesion revascularization, and the composite
of all-cause mortality or recurrent myocardial in-
farction. Additional secondary end points, for
which data were also obtained from the registries
and assessed during the index hospitalization,
included complications of PCI, stroke or neuro-
logic complications, heart failure, and length of
stay in the hospital. Definitions of the end points
are provided in the Supplementary Appendix. No
study-specific clinical follow-up assessment was
performed.
Statistical Analysis
On the basis of actual data on mortality from all
patients with STEMI who underwent PCI in Swe-
den between 2008 and 2009, we assumed that
the 1-month mortality with PCI alone would be
6.3%. We calculated that 456 events would need
to occur for the study to have 80% power to de-
tect a hazard ratio for death of at least 1.30 with
PCI alone as compared with PCI plus thrombus
aspiration, at a two-sided significance level of 5%.
To meet this goal, we planned to include 4886
patients (with a total planned enrollment of 5000
to account for crossover and device failure, as-
suming no loss to follow-up).
15
When enrollment approached 5000 patients,
the 30-day mortality (estimated without knowl-
edge of treatment assignments) was observed to
be lower than expected (2.9%) in the study co-
hort. Therefore, the steering committee amend-
ed the protocol to increase the sample size and
adopt a group-sequential design. Taking into con-
sideration the hazard ratio of 1.95 for death from
cardiac causes at 30 days in the TAPAS study,
6,13
and assuming 30-day mortality of 3.5% with
conventional PCI, an odds ratio for death with
PCI alone as compared with PCI with thrombus
aspiration of at least 1.5, and one interim analy-
sis performed when 67% of the total sample had
been enrolled in which the stopping boundary
for significance was set at a P value of less than
0.01 and for futility (nonbinding) at a P value of
more than 0.493, it was calculated that with
7138 patients, the study would have 80% power
to obtain a significant result at the 5% level with
the use of two-sided tests. The data monitoring
committee conducted the interim analysis in
August 2012 on data from 4802 patients and
recommended that the study continue.
The results were analyzed according to the in-
tention-to-treat principle. In a post hoc per-pro-
tocol analysis, we also compared the patients in
the thrombus-aspiration group who underwent
thrombus aspiration with the patients in the PCI-
only group who did not. The time to death within
30 days after PCI according to study group is pre-
sented in a Kaplan–Meier plot. Hazard ratios for
the primary end point and for all end points as-
sessed through 30 days were calculated with the
use of a Cox proportional-hazards model with
treatment as the only factor and are shown with
the nominal 95% confidence interval from the
Cox model and the nominal two-sided P value
from a log-rank test. Odds ratios for end points
assessed during the index hospitalization were
estimated from a logistic-regression model, with
P values calculated with the use of Pearson’s chi-
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The
new england journal
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medicine
n engl j med 369;17 nejm.org october 24, 2013
1590
square test. Subgroup analyses were performed
by including an interaction term in the propor-
tional-hazards model. All analyses were performed
with the use of SAS software, version 9.3 (SAS
Institute). According to the interim analysis plan,
a two-tailed P value of less than 0.0471 was con-
sidered to indicate statistical significance with
respect to the primary variable.
Results
Study Population
All 29 PCI centers in Sweden as well as 1 in Ice-
land and 1 in Denmark participated in the trial.
During the study period, 11,709 patients with
STEMI in Sweden and Iceland underwent PCI and
were registered in SCAAR. Of these, 7012 were
enrolled in the trial. An additional 247 patients
were enrolled from the center in Denmark, for a
total of 7259 patients (Fig. 1). Fifteen erroneous
enrollments (patients initially reported as having
STEMI, for whom the diagnosis was changed by
the operator and no PCI was performed) were
excluded from the database, leaving 7244 patients
who underwent randomization.
The baseline clinical characteristics of all the
patients who underwent randomization (including
patients at all the centers) and all the patients
who did not undergo randomization (including
patients at all the centers except the center in
Denmark) are listed in
Table 1
. Procedural char-
acteristics are listed in Tables S1 and S2 in the
Supplementary Appendix. A total of 60% of the
patients presenting with STEMI and referred for
PCI in Sweden and Iceland underwent randomiza-
tion in the TASTE trial during the study period.
None of the patients who underwent random-
ization were lost to follow-up with respect to the
primary end point. However, six patients withdrew
consent and were included in the analysis only
until the date of withdrawal. Among patients who
did not undergo randomization, we obtained com-
plete follow-up data on all the patients in Sweden
and follow-up data for all variables except mortal-
ity on patients in Iceland, but we did not obtain
follow-up data on patients in Denmark who did
not undergo randomization.
Procedural Data
After undergoing randomization, 93.9% of the pa-
tients in the thrombus-aspiration group under-
went thrombus aspiration; in addition, 4.9% of the
patients in the PCI-only group underwent throm-
bus aspiration (Table S2 in the Supplementary
Appendix). Patients were treated according to in-
ternational guidelines, with high proportions of
patients receiving platelet inhibitors and anti-
thrombotic agents before and during the proce-
dure and with a high proportion of PCIs per-
formed through a radial access and including
implantation of drug-eluting stents.
Clinical Outcomes
By 30 days, 2.8% of the patients randomly as-
signed to thrombus aspiration (103 of 3621 pa-
tients) and 3.0% of the patients randomly assigned
to PCI only (110 of 3623 patients) had died (haz-
ard ratio with thrombus aspiration, 0.94; 95%
confidence interval [CI], 0.72 to 1.22; P = 0.63)
(Fig. 2A and
Table 2
). The 30-day mortality in the
per-protocol analysis was 2.6% (88 of 3399 pa-
tients) with thrombus aspiration and 2.9% (101
of 3445 patients) with PCI only (hazard ratio, 0.88;
95% CI, 0.66 to 1.17; P = 0.38).
The rate of rehospitalization due to reinfarc-
tion was 0.5% in the thrombus-aspiration group
(19 patients) and 0.9% in the PCI-only group (31
patients) (hazard ratio, 0.61; 95% CI, 0.34 to 1.07;
P = 0.09) (Fig. 2B). The rates in the per-protocol
analysis were 0.5% (18 of 3399 patients) and 0.8%
(27 of 3445 patients) in the two groups, respec-
tively (hazard ratio, 0.67; 95% CI, 0.36 to 1.2;
P = 0.19). The rates of stent thrombosis, target-
lesion revascularization, and target-vessel revas-
cularization did not differ significantly between
the groups. There was no significant between-
group difference in the rate of stroke or neuro-
logic complications, perforation or tamponade,
or heart failure or left ventricular dysfunction at
the time of discharge, nor was there a significant
difference in the length of stay in the hospital.
The primary outcome of all-cause mortality at
30 days was consistent across all prespecified
subgroups, including patients with a high risk of
thrombosis, such as those with Thrombolysis in
Myocardial Infarction (TIMI) flow grade 0 or 1,
those with thrombus grade 4 or 5 (on a scale of
0 to 5, with higher grades indicating a larger
thrombus), and smokers (Fig. 3).
Cohort That Did Not Undergo Randomization
The reasons indicated by the operators for not
enrolling patients were as follows: inability of the
patient to provide oral informed consent (38% of
patients who did not undergo randomization),
thrombus aspiration not possible (16%), thrombus
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