European Heart Journal (2018) 39, 2730–2739 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehy326 Acute coronary syndromes

Oxygen therapy in ST-elevation myocardial

infarction
Robin Hofmann1*, Nils Witt1, Bo Lagerqvist2, Tomas Jernberg3, Bertil Lindahl2,4,

Downloaded from https://academic.oup.com/eurheartj/article-abstract/39/29/2730/5037999 by guest on 13 August 2019

David Erlinge5, Johan Herlitz6,7, Joakim Alfredsson8,9, Rikard Linder3,
Elmir Omerovic6, Oskar Angerås6, Dimitrios Venetsanos8,9, Thomas Kellerth10,
David Sparv5, Jörg Lauermann11, Neshro Barmano11, Dinos Verouhis12,13,
Ollie Östlund4, Leif Svensson12,14, and Stefan K. James2,4, for the DETO2X-
SWEDEHEART Investigators
1
Division of Cardiology, Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Sjukhusbacken 10, 11883 Stockholm, Sweden; 2Cardiology,
Department of Medical Sciences, Uppsala University, Akademiska sjukhuset, Entrance 40, floor 5, 75185 Uppsala, Sweden; 3Cardiology, Department of Clinical Sciences,
Karolinska Institutet, Danderyd Hospital, Mörbygårdsvägen 5, 18288 Stockholm, Sweden; 4Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 38,
75185 Uppsala, Sweden; 5Department of Cardiology, Clinical Sciences, Lund University, 22185 Lund, Sweden; 6Department of Cardiology, Sahlgrenska University Hospital, 41345
Gothenburg, Sweden; 7Department of Health Sciences, University of Borås, 50190 Borås, Sweden; 8Department of Medical and Health Sciences, Linköping University,
Sandbäcksgatan 7, 58183 Linköping, Sweden; 9Department of Cardiology, Linköping University Hospital, 58185 Linköping, Sweden; 10Department of Cardiology, Örebro
University Hospital, 70185 Örebro, Sweden; 11Division of Cardiology, Department of Internal Medicine, Ryhov Hospital, Sjukhusgatan, 55305 Jönköping, Sweden; 12Department
of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden; 13Department of Cardiology, Karolinska University Hospital, 17176
Stockholm, Sweden; and 14Centre for Resuscitation Science, Karolinska Institutet, Södersjukhuset, Jägargatan 20, 11883 Stockholm, Sweden

Received 29 January 2018; revised 16 March 2018; editorial decision 17 May 2018; accepted 21 May 2018; online publish-ahead-of-print 14 June 2018

Aims To determine whether supplemental oxygen in patients with ST-elevation myocardial infarction (STEMI) impacts
on procedure-related and clinical outcomes.
...................................................................................................................................................................................................
Methods The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial random-
and results ized patients with suspected myocardial infarction (MI) to receive oxygen at 6 L/min for 6–12 h or ambient air. In
this pre-specified analysis, we included only STEMI patients who underwent percutaneous coronary intervention
(PCI). In total, 2807 patients were included, 1361 assigned to receive oxygen, and 1446 assigned to ambient air.
The pre-specified primary composite endpoint of all-cause death, rehospitalization with MI, cardiogenic shock, or
stent thrombosis at 1 year occurred in 6.3% (86 of 1361) of patients allocated to oxygen compared to 7.5% (108
of 1446) allocated to ambient air [hazard ratio (HR) 0.85, 95% confidence interval (95% CI) 0.64–1.13; P = 0.27].
There was no difference in the rate of death from any cause (HR 0.86, 95% CI 0.61–1.22; P = 0.41), rate of rehospi-
talization for MI (HR 0.92, 95% CI 0.57–1.48; P = 0.73), rehospitalization for cardiogenic shock (HR 1.05, 95% CI
0.21–5.22; P = 0.95), or stent thrombosis (HR 1.27, 95% CI 0.46–3.51; P = 0.64). The primary composite endpoint
was consistent across all subgroups, as well as at different time points, such as during hospital stay, at 30 days and
the total duration of follow-up up to 1356 days.
...................................................................................................................................................................................................
Conclusions Routine use of supplemental oxygen in normoxemic patients with STEMI undergoing primary PCI did not signifi-
cantly affect 1-year all-cause death, rehospitalization with MI, cardiogenic shock, or stent thrombosis.
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Keywords Oxygen • ST-elevation myocardial infarction • Percutaneous coronary intervention • Registry-based randomized
clinical trial • Reactive oxygen species • Reperfusion injury

* Corresponding author. Tel: þ46-8-6161000, Fax: þ46-8-6163031, Email: robin.hofmann@sll.se

Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
Oxygen therapy in STEMI
.. the authors who vouch for the data and all analyses, and for the fidelity of
Introduction
Supplemental oxygen therapy has been a cornerstone of supportive
care in ST-elevation myocardial infarction (STEMI) for more than a
century and is widely endorsed by international guidelines.1,2 Oxygen
is considered to increase oxygen supply to the ischaemic myocar-
dium and thereby improve cardiac metabolism, reduce infarct size,
prevent circulatory chock, and ultimately, improve patient outcomes.
Small clinical trials indicated positive results on surrogate end-
points,3–5 but no trial so far has been large enough to evaluate hard
clinical endpoints. On the contrary, data from a recent clinical trial6
and experimental studies have demonstrated negative effects of oxy-
gen therapy on cardio-circulatory haemodynamics due to direct
hyperoxaemic vasoconstriction and increased production of reactive
oxygen species.7,8 A dose-dependent relationship between oxygen
exposure and risk for myocardial injury has been proposed.9 In the
setting of STEMI and acute primary percutaneous coronary interven-
tion (PCI), reopening of the occluded vessel is closely associated with
reperfusion injury, which can lead to arrhythmias, contractile dysfunc-
tion, microvascular impairment, and irreversible myocardial
damage,10 all enhanced by reactive oxygen species.11 Further, vaso-
constriction may lead to underestimation of the diameter of the cul-
prit coronary artery and undersizing of the coronary stent with
successive long-term risk of stent thrombosis, restenosis, and need
for target vessel revascularization.12,13
The DETermination of the role of Oxygen in suspected Acute
Myocardial Infarction (DETO2X-AMI) trial randomized patients with
suspected myocardial infarction (MI) to receive oxygen at 6 L/min for
6–12 h or ambient air. The primary endpoint of all-cause death at
1 year as well as secondary endpoints of rehospitalization with MI
and cardiac troponin T levels did not show any significant difference
between the two study groups.14
If routine oxygen therapy affects hard clinical endpoints or proced-
ure-related outcomes in STEMI patients undergoing PCI remains
uncertain.6,15,16
In this pre-specified subgroup analysis, we therefore aimed to
evaluate whether supplemental oxygen reduces major adverse car-
diac events and procedure-related clinical outcomes at 1 year in
STEMI patients undergoing PCI.
Methods
Study design
The DETO2X-AMI trial was a nationwide, multicentre, open-label, regis-
try-based randomized clinical trial (RRCT) comparing routine supplemental
oxygen therapy to ambient air in patients with suspected AMI. The study
used the Swedish Web System for Enhancement and Development of
Evidence-based Care in Heart Disease Evaluated According to
Recommended Therapies (SWEDEHEART)17 registry for patient recruit-
ment and trial procedures and follow-up.
The trial design,18 methods, and first results have been described in de-
tail previously.14 The ethics committee and the medical products agency
of Sweden approved the study. Trial sponsor was Karolinska Institutet,
Stockholm, Sweden. Uppsala Clinical Research Center at Uppsala
University, Sweden, was responsible for trial administration, data manage-
ment, and statistical analyses and is running the SWEDEHEART registry.
The study was designed and conducted, and the manuscript written, by
2731
..
.. this report to the trial protocol and statistical analysis plan which are avail-
.. able with the full text of this article online. The funding agencies had no
..
.. access to the study data and no role in trial design, implementation, or
.. reporting.
..
..
.. Patient population
..
.. Patients presenting to the ambulance service, emergency department,
.. coronary care unit, or catheterization laboratory of participating hospitals
.. were evaluated for enrolment. Trial participants were required to be
..
.. 30 years of age or older and to have symptoms suggestive of AMI (defined
.. as chest pain or shortness of breath) for <6 h, oxygen saturation of >_90%
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..
.. on pulse oximetry, and either electrocardiogram (ECG) changes indicat-
.. ing ischaemia13 or elevated cardiac troponin on admission (above the lo-
.. cally defined decision limit for MI). To allow complete follow-up through
..
.. the Swedish National Population Registry, only Swedish citizens with a
.. unique personal identification number were enrolled.
..
.. Patients with ongoing oxygen therapy or cardiac arrest prior to enrol-
.. ment were excluded. If supplemental oxygen therapy had been adminis-
.. tered for <20 min before evaluation for enrolment, a new evaluation was
..
.. allowed after discontinuation of oxygen delivery and 10 min of washout.
.. For this analysis, only patients with discharge diagnosis STEMI with per-
..
.. formed PCI were evaluated, all others excluded.
..
..
.. Study procedures
.. After providing initial oral consent, patients who fulfilled all inclusion cri-
..
.. teria and had no exclusion criteria were randomly assigned, in a 1:1 ratio,
.. to either oxygen therapy at 6 L/min for 6–12 h delivered by open face
..
.. mask or ambient air. Randomization was performed by means of an on-
.. line randomization module following a computer-generated list within
.. the SWEDEHEART database. The study treatment was initiated directly
..
.. on site immediately after randomization.
.. All patients were asked to confirm their agreement to participate by
..
.. providing written informed consent within 24 h. All patients were treated
.. according to standard of care. Oxygen saturation was documented at the
.. beginning and the end of the randomized treatment period. If clinically
..
.. indicated, particularly in cases of hypoxaemia (defined as oxygen satur-
.. ation below 90%) of any cause, patients received supplemental oxygen
..
.. outside the protocol, which was reported separately.
..
..
.. Endpoints and definitions
.. Data on clinical outcomes and follow-up were obtained from
..
.. SWEDEHEART and national health registries. Detailed procedural and
.. outcome data were obtained from the national comprehensive Swedish
.. Coronary Angiography and Angioplasty Registry (SCAAR) a part of
..
.. SWEDEHEART. The present analysis regards the first major subgroup of
.. the DETO2X trial. For this study, the pre-specified primary endpoint was
..
.. a composite of all-cause death, rehospitalization with MI, cardiogenic
.. shock, or stent thrombosis at 1 year [major adverse cardiac event
.. (MACE1)]. The secondary endpoint was a composite of MACE1 and tar-
..
.. get vessel revascularization (MACE2). The primary objective was also
.. analysed in relevant subgroups and at different points in time such as dur-
..
.. ing hospital stay, at 30 days and the total follow-up time.
..
.. sis We included patients who underwent PCI and had a final STEMI diagno-
.. in SWEDEHEART defined according to International Classification of
.. Diseases 10th revision (ICD-10) code I.21 or I.22 with ST-elevation19 or
.. left bundle branch block on the admission ECG.
..
.. Mortality data were obtained from the Swedish population regis-
.. try, including vital status of all Swedish citizens. Data on rehospitali-
.. zation with MI were obtained from the SWEDEHEART registry, and
..
. defined according to ICD codes I.21 and I.22. Rehospitalization with
2732 R. Hofmann et al.

Table 1 Baseline characteristics and clinical presentation in the According to Treatment Group and Randomisation
Status

Oxygen Unknown/ Ambient air Unknown/ Not enrolled during the

(n 5 1361) missing, n (%) (n 5 1446) missing, n (%) trial period (n 5 4951)
....................................................................................................................................................................................................................
Demographics, n (%)
Age (years) median (IQR) 67 (58–75) 0 67 (59–75) 0 68 (59–77)
Male sex 969 (71.2) 0 1067 (73.8) 0 3486 (70.4)
Risk factors, n (%)
Body-mass indexa 27.1 ± 4.4 19 (1.4) 26.9 ± 4.1 26 (1.8) 27 ± 4.9

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Current smoking 381 (28.0) 18 (1.3) 418 (28.9) 15 (1.0) 1332 (26.9)
Hypertensionb 570 (41.9) 0 630 (43.6) 0 2211 (44.7)
Diabetes mellitus 209 (15.4) 0 238 (16.5) 0 913 (18.4)
Previous CV disease, n (%)
Myocardial infarction 167 (12.3) 0 188 (13.0) 0 824 (16.6)
PCI 145 (10.7) 0 152 (10.5) 0 623 (12.6)
CABG 32 (2.4) 1 (0.1) 38 (2.6) 2 (0.1) 174 (3.5)
Presentation
Time from symptom onset to randomization 168 (104–300) 43 (3.2) 174 (102–328) 47 (3.3) —
(min) median (IQR)
Time from symptom onset to PCI (min) 183 (124–327) 48 (3.5) 192 (125–327) 51 (3.5) 179 (115–332)
median (IQR)
Time from diagnostic ECG to randomization 45 (22–77) 60 (4.4) 45 (24–75) 79 (5.5) —
(min) median (IQR)
Time from diagnostic ECG to PCI (min), 61 (45–86) 32 (2.4) 63 (46–86) 41 (2.8) 62 (44–88)
median (IQR)
Time from randomization to PCI (min) 15 (3–40) 5 (0.4) 15 (3–40) 8 (0.6) —
median (IQR)
Ambulance transportation, n (%) 1072 (78.7) 5 (0.4) 1122 (77.6) 3 (0.2) 4053 (81.8)
Systolic blood pressure (mmHg)b 146.8 ± 27.9 2 (0.1) 144.0 ± 28.0 2 (0.1) 138.6 ± 33.1
Heart rate (b.p.m.) 76.3 ± 18.3 2 (0.1) 75.8 ± 18.1 2 (0.1) 78.6 ± 23.2
Oxygen saturation (%), median (IQR) 97 (95–98) 0 97 (95–98) 0 —
Causes of admission
Chest pain 1325 (97.4) 1397 (96.6) 4347 (87.8)
Dyspnoea 9 (0.7) 18 (1.2) 114 (2.3)
Cardiac arrest 1 (0.1) 0 242 (4.9)
Medication on admission, n (%)
Aspirin 241 (17.7) 8 (0.6) 276 (19.1) 13 (0.9) 1143 (23.1)
P2Y12 receptor inhibitors 41 (3.0) 8 (0.6) 43 (3.0) 15 (1.1) 164 (3.3)
Beta-blocker 315 (23.1) 18 (1.3) 322 (22.3) 21 (1.5) 1319 (26.6)
Statins 259 (19.0) 12 281 (19.4) 13 (0.9) 1044 (21.1)
ACE-inhibitors or AT II-blockers 386 (28.4) 18 (1.3) 425 (29.4) 24 (1.7) 1451 (29.3)
Calcium-blockers 226 (16.6) 16 237 (16.4) 23 (1.6) 831 (16.8)
Diuretics 143 (10.5) 18 (1.3) 143 (9.9) 20 (1.4) 648 (13.1)

Plus–minus values are mean ± SD. There were no significant differences in baseline characteristics between oxygen group and the ambient-air group except as otherwise noted.
— denotes oxygen saturation at presentation is not registered in SWEDEHEART.
ACE, angiotensin converting enzyme; AT, angiotensin; CABG, coronary artery bypass graft; CV, cardiovascular; DETO2X-STEMI, DETermination of the role of OXygen in St-
segment Elevated Myocardial Infarction; ECG, electrocardiogram; IQR, interquartile range; PCI, percutaneous coronary intervention.
a
The body-mass index (the weight in kilograms divided by the square of the height in meters).
b
P < 0.05 for the comparison between the oxygen group and the ambient-air group.

cardiogenic shock was defined as cardiogenic shock on arrival or

.. was defined as any repeat PCI procedure or surgical bypass of any
..
during hospitalization or Killip Class III–IV in the catheterization la- .. segment of the target vessel after the index procedure. Target le-
boratory. Definite stent thrombosis was obtained from .. sion revascularization was defined as any repeat PCI intervention of
..
SWEDEHEART and was defined in accordance with the Academic .. the target segment or surgical bypass of the target vessel after the
Research Consortium definition.20 Target vessel revascularization .. index procedure.
Oxygen therapy in STEMI 2733

Table 2 In-hospital trial procedural data, medication, PCI procedural data, and complications According to
Treatment Group and Randomisation Status

Oxygen Ambient air P-value Not enrolled during

(n 5 1361) (n 5 1446) the trial period (n 5 4951)
....................................................................................................................................................................................................................
Trial procedural data
Duration of oxygen therapy (h) median (IQR) 10.36 (6.02–12.00) x —
Oxygen saturation at end of treatment period (%) median (IQR)a 99 (97–100) 97 (95–98) 0.25 —
Therapy before PCI, n (%)
Aspirin 1212 (89.1) 1311 (90.7) 0.17 4108 (83.0)
Clopidogrela

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107 (7.9) 155 (10.7) 0.01 583 (11.8)
Ticagrelor 988 (72.6) 1023 (70.7) 0.26 3015 (60.9)
Prasugrel 65 (4.8) 75 (5.2) 0.62 189 (3.8)
Heparin 774 (56.9) 813 (56.2) 0.67 1958 (39.5)
Fondaparinux 43 (3.2) 51 (3.5) 0.59 324 (6.5)
Thrombolysis 6 (0.4) 11 (0.8) 0.28 54 (1.1)
Therapy during PCI, n (%)
Heparin 897 (65.9) 982 (67.9) 0.26 3714 (75.0)
Bivalirudin 697 (51.2) 725 (50.1) 0.55 2539 (51.3)
Abciximab 40 (2.9) 50 (3.5) 0.44 155 (3.1)
Eptifibatide 31 (2.3) 35 (2.4) 0.90 157 (3.2)
Tirofiban 136 (10.0) 155 (10.7) 0.53 411 (8.3)
PCI procedural data
Radial puncture, n (%) 1179 (86.6) 1233 (85.3) 0.30 3838 (77.5)
Max stent diameter (mm) median (IQR) 3.0 (2.75–3.5) 3.0 (2.75–3.5) 0.49 3.0 (2.75–3.5)
Coronary arteries treated, n (%) 0.45
1 1211 (89.0) 1278 (88.4) 4317 (87.2)
2 136 (10.0) 144 (10.0) 549 (11.1)
3 14 (1.0) 23 (1.6) 81 (1.6)
Total stent length (mm) median (IQR) 24.00 (18.00–38.00) 26.00 (18.00–39.00) 0.29 26.00 (18.00–40.00)
Complete revascularization, n (%) 835 (61.4) 864 (59.8) 0.33 2849 (57.5)
Acute heart failure, n (%)
Use of iv diuretics 158 (11.6) 177 (12.2) 0.61 1117 (22.6)
Use of iv inotropesa 35 (2.6) 58 (4.0) 0.03 448 (9.0)
Use of iv nitroglycerin 85 (6.2) 92 (6.4) 0.90 403 (8.1)
Cardiogenic shock 25 (1.8) 33 (2.3) 0.41 341 (6.9)
Complications, n (%)
Reinfarction 12 (0.9) 11 (0.8) 0.72 50 (1.0)
New-onset atrial fibrillation 59 (4.3) 63 (4.4) 0.99 337 (6.8)
AV-block II–III 33 (2.4) 34 (2.4) 0.91 143 (2.9)
Cardiac arrest 56 (4.1) 51 (3.5) 0.41 441 (8.9)
Death 26 (1.9) 29 (2.0) 0.86 422 (8.5)

Plus–minus values are mean ± SD. There were no significant differences in trial procedural data, medication, procedures and complications during the hospitalization period; or
discharge diagnoses between the patients assigned to oxygen or the patients assigned to ambient air except as otherwise noted. — denotes in-hospital oxygen saturation is not
registered in SWEDEHEART.
AV, atrioventricular; IQR, interquartile range; PCI, percutaneous coronary intervention; x, not applicable.
a
P < 0.05 for the comparison between the oxygen group and the ambient-air group.

The end of follow-up was 30 December 2016, 365 days after random-
.. treatment group information were available for monitoring of
..
ization of the last patient. No central adjudication or study-specific patient .. study progress throughout the trial.
follow-up was performed. ..
..
The local study team on site and steering committee were .. Statistical analysis
blinded to treatment comparisons until locking of the database, .. The sample-size calculations for the overall trial have been described pre-
by restricting access to the randomization list to authorized
.. viously.18 There was no pre-specified power calculation for the present
..
SWEDEHEART registry personnel. Accumulated data without . subgroup.
2734 R. Hofmann et al.

Table 3 Endpoints According to Treatment Group and Randomisation Status during hospitalization, at 30 days, at
365 days, and the entire follow-up (maximum 1357 days) post-randomization

Endpoint Oxygen Ambient air Hazard ratio P-value Not enrolled during
(n 5 1361) (n 5 1446) (95% CI) the trial period (n 5 4951)
....................................................................................................................................................................................................................
1357 days, n (%)
MACE1 140 (10.3) 167 (11.5) 0.90 (0.72–1.13) 0.38 1040 (21.0)
MACE2 194 (14.3) 216 (14.9) 0.96 (0.79–1.17) 0.71 1219 (24.6)
All-cause death 86 (6.3) 100 (6.9) 0.94 (0.70–1.25) 0.67 828 (16.7)
Rehospitalization with MI 6.1 (4.5) 70 (4.8) 0.93 (0.66–1.32) 0.70 241 (4.9)

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Rehospitalization with cardiogenic shock 6 (0.4) 5 (0.3) 1.28 (0.39–4.19) 0.67 18 (0.4)
Stent thrombosis 13 (1.0) 13 (0.9) 1.09 (0.5–2.35) 0.83 46 (0.9)
Target vessel revascularization 89 (6.5) 89 (6.2) 1.08 (0.80–1.45) 0.62 292 (5.9)
Target lesion revascularization 58 (4.3) 58 (4.0) 1.08 (0.75–1.55) 0.70 194 (3.9)
365 days, n (%)
MACE1 86 (6.3) 108 (7.5) 0.85 (0.64–1.13) 0.27 821 (16.6)
MACE2 130 (9.6) 153 (10.6) 0.91 (0.72–1.14) 0.41 988 (20.0)
All-cause death 57 (4.2) 71 (4.9) 0.86 (0.61–1.22) 0.41 665 (13.4)
Rehospitalization with MI 32 (2.4) 37 (2.6) 0.92 (0.57–1.48) 0.73 163 (3.3)
Rehospitalization with cardiogenic shock 3 (0.2) 3 (0.2) 1.05 (0.21–5.22) 0.95 14 (0.3)
Stent thrombosis 8 (0.6) 7 (0.5) 1.27 (0.46–3.51) 0.64 35 (0.7)
Target vessel revascularization 68 (5.0) 65 (4.5) 1.12 (0.80–1.57) 0.51 250 (5.0)
Target lesion revascularization 45 (3.3) 39 (2.7) 1.24 (0.81–1.90) 0.33 165 (3.3)
30 days, n (%)
MACE1 56 (4.1) 50 (3.5) 1.21 (0.83–1.78) 0.31 538 (10.9)
MACE2 81 (6.0) 78 (5.4) 1.12 (0.82–1.53) 0.48 636 (12.8)
All-cause death 39 (2.9) 38 (2.6) 1.11 (0.71–1.74) 0.64 473 (9.6)
Rehospitalization with MI 17 (1.2) 13 (0.9) 1.43 (0.69–2.95) 0.33 57 (1.2)
Rehospitalization with cardiogenic shock 1 (0.1) 0 — — 6 (0.1)
Stent thrombosis 8 (0.6) 4 (0.3) 2.25 (0.68–7.46) 0.19 22 (0.4)
Target vessel revascularization 38 (2.8) 34 (2.4) 1.21 (0.76–1.92) 0.42 136 (2.7)
Target lesion revascularization 26 (1.9) 21 (1.5) 1.34 (0.76–2.39) 0.31 98 (2.0)
During hospital stay
hs-Troponin T, n (%) 1149 (82.6) 1193 (82.5) 0.33 3997 (80.7)
Median (ng/L) (IQR) 1780 (657–4717) 1930 (696–4666) 2100 (622–5570)

MACE1 was the primary composite endpoint of all-cause death, reinfarction, cardiogenic shock, or stent thrombosis.
MACE2 was the secondary composite endpoint of all-cause death, reinfarction, cardiogenic shock, stent thrombosis, or target vessel revascularization.
CI, confidence interval; MACE, major adverse cardiac event; MI, myocardial infarction.

..
The results were analysed according to the intention-to-treat prin- .. Results
ciple. Time to event within 365 days and the entire follow-up with a max-
..
..
imum of 1357 days (median duration 752 days) post-randomization is .. Study population
presented in the Kaplan–Meier curves. Hazard ratios (HRs) between ..
.. Of the 6629 patients enrolled in the main trial, 2807 (42%) had
treatment groups were calculated using a Cox proportional hazard .. a discharge diagnosis of STEMI with primary PCI performed
model, adjusted for age in years (as a linear covariate on the log-hazard ..
scale) and sex. Estimates of treatment differences are presented with .. and were included in this analysis. In all, 78% of these patients
.. arrived by ambulance to the hospital, 61% were admitted dir-
two-tailed 95% confidence intervals (95% CI) and associated P-values. A ..
two-tailed P-value of <0.05 was considered statistically significant. Eleven .. ectly to the coronary care unit or catheterization laboratory,
pre-specified subgroup analyses were performed using proportional haz-
.. and the remaining 17% through the emergency department.
..
ards models with age and sex adjustment and formal tests for interaction. .. Overall, 2722 (97%) patients were enrolled due to chest pain
All analyses were conducted with SAS v.9.4 (SAS Institute Inc., Cary,
.. and 27 (1%) due to shortness of breath as the qualifying
..
NC, USA). .. symptom.
Oxygen therapy in STEMI 2735

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Figure 1 Enrolment, randomization, and follow-up. Eligible patients were evaluated for inclusion. Shown are the numbers of patients who were
enrolled in the main study, randomly assigned to a study group, kept in this ST-elevation myocardial infarction sub group analysis and followed up dur-
ing the study period; as well as ST-elevation myocardial infarction patients at participating sites not randomized during the trial period. AMI, acute
myocardial infarction; DETO2X-AMI, DETermination of the role of Oxygen in Acute Myocardial Infarction; ITT, intention-to-treat; STEMI, ST-eleva-
tion myocardial infarction.

..
Procedural data .. from symptom onset and diagnostic ECG to randomization, the dur-
At the time of randomization, the median oxygen saturation was .. ation from symptom onset and diagnostic ECG to PCI, and the dur-
..
97.0% [interquartile range (IQR) 95.0–98.0%] in both groups. All .. ation from randomization to PCI was similar between the two
randomized patients were followed according to the intention-to- .. groups. The median duration of oxygen therapy was 10.36 (IQR
..
treat principle, 1361 allocated to oxygen which was initiated immedi- .. 6.02–12.00) h with a median oxygen saturation of 99.0% (IQR 97.0–
ately after randomization, 1446 allocated to ambient air. The duration .. 100%) in patients assigned to oxygen and 97.0% (IQR 95.0–98.0%) in
2736 R. Hofmann et al.

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Figure 2 The Kaplan–Meier curves for the composite of all-cause death, rehospitalization with myocardial infarction, cardiogenic shock, or stent
thrombosis (major adverse cardiac event 1) up to 365 days. The Kaplan–Meier curves are shown for the cumulative probability of major adverse car-
diac event 1 up to 365 days after randomization for patients assigned to oxygen or ambient air. The insets show the same data on an enlarged y-axis.
MACE 1, major adverse cardiac event 1.

Figure 3 The Kaplan–Meier curves for the composite of all-cause death, rehospitalization with myocardial infarction, cardiogenic shock, or stent
thrombosis (major adverse cardiac event 1) for the entire follow-up. The Kaplan–Meier curves are shown for the cumulative probability of major ad-
verse cardiac event 1 for the entire follow-up (median duration 752 days) with a maximum of 1357 days after randomization for patients assigned to
oxygen or air (post hoc analysis). The insets show the same data on an enlarged y-axis. MACE 1, major adverse cardiac event 1.
Oxygen therapy in STEMI 2737

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Figure 4 Hazard ratios for the primary composite endpoint major adverse cardiac event 1 in subgroups of patients. Hazard rations are shown for
the primary composite endpoint of all-cause death, rehospitalization with myocardial infarction, cardiogenic shock, or stent thrombosis (major ad-
verse cardiac event 1) within 365 days after randomization. CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio; MI, myocardial in-
farction; PCI, percutaneous coronary intervention.

patients assigned to ambient air at the end of the treatment period. .. was 6.3% (86 of 1361) in the patients allocated to oxygen compared
..
Hypoxaemia occurred in 236 patients (8.4%) in total, 44 (3.2%) in the .. to 7.5% (108 of 1446) patients allocated to ambient air (HR 0.85,
patients assigned to oxygen, 192 (13.3%) in the patients assigned to
.. 95% CI 0.64–1.13; P = 0.27) (Figure 2 and Table 3). No significant
..
ambient air. .. interaction between the duration of therapy and the randomized
In total, 122 (4.3%) patients did not complete the allocated treat-
.. groups on the primary endpoint was found (P = 0.22).
..
ment period, 86 (6.3%) patients allocated to oxygen, and 36 (2.5%) .. The incidence of the composite of all-cause death, rehospitaliza-
allocated to ambient air. Reasons for not fulfilling randomized therapy
.. tion with MI, cardiogenic shock, stent thrombosis, or target vessel
..
were as follows (oxygen/ambient air): withdrawal 4.1%/0.3%; early .. revascularization at 1 year (MACE2) was 9.6% (130 of 1361) in the
discharge (0%/0.3%); change of clinical circumstances 0.9%/0.4%; mis-
.. patients allocated to oxygen compared to 10.6% (153 of 1446)
..
takes (technical, communication) 1.0%/1.3% (Figure 1). .. patients allocated to ambient air (HR 0.91, 95% CI 0.72–1.14;
..
Baseline characteristics and clinical presentation for all randomized .. P = 0.41) (Table 3).
and non-randomized STEMI patients at participating sites during the .. At 1 year, the rate of death from any cause was 4.2% vs. 4.9% in
..
trial period are listed in Table 1. In-hospital procedural characteristics .. the two groups (oxygen/ambient air), respectively (HR 0.86, 95% CI
and complications are listed in Table 2. Endpoints are summarized in .. 0.61–1.22; P = 0.41), the rate of rehospitalization with MI was 2.4% vs.
..
Table 3. .. 2.6%, respectively (HR 0.92, 95% CI 0.57–1.48; P = 0.73), the rate of
.. rehospitalization with cardiogenic shock was 0.2% vs. 0.2%, respect-
..
Clinical endpoints .. ively (HR 1.05, 95% CI 0.21–5.22; P = 0.95), and the rate of stent
The incidence of the composite of all-cause death, rehospitalization
.. thrombosis was 0.6% vs. 0.5%, respectively (HR 1.27, 95% CI 0.46–
..
with MI, cardiogenic shock, or stent thrombosis at 1 year (MACE1) . 3.51; P = 0.64) (Table 3).
2738 R. Hofmann et al.

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Take home figure The Kaplan–Meier curves for the composite of all-cause death, rehospitalization with myocardial infarction, cardiogenic
shock, or stent thrombosis [major adverse cardiac event (MACE1)] up to 365 days. Enrolled ST-elevation myocardial infarction patients were
randomized to either oxygen therapy at a moderate flowrate of 6 L/min for a median of 10.36 h or ambient air. The time from symptom onset to ran-
domization and PCI was similar between the groups. The pre-specified primary composite endpoint of all-cause death, rehospitalization with myocar-
dial infarction, cardiogenic shock, or stent thrombosis at 1 year occurred in 6.3% (86 of 1361) of patients allocated to oxygen compared to 7.5% (108
of 1446) allocated to ambient air (hazard ratio 0.85, 95% confidence interval 0.64–1.13; P = 0.27). Routine use of supplemental oxygen in normoxe-
mic patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention did not significantly affect 1-year all-
cause death, rehospitalization with myocardial infarction, cardiogenic shock, or stent thrombosis. MACE, major adverse cardiac event.

The median duration of follow-up from the first included pa- ..

.. Outcomes for patients not enrolled in
tient to 1-year follow-up of the last patient was 752 days (IQR
573–984) with a maximum of 1357 days. When the entire
follow-up period was analysed, the incidence of the composite
of all-cause death, rehospitalization with MI, cardiogenic shock,
or stent thrombosis (MACE1) was 10.3% (140 of 1361) in
patients allocated to oxygen compared to 11.5% (167 of 1446)
in patients allocated to ambient air (HR 0.90, 95% CI 0.72–1.13;
P = 0.38) (Figure 3 and Table 3). The rate of death was 6.3% (86
of 1361) in patients allocated to oxygen vs. 6.9% (100 of 1446)
in the patients allocated to ambient air (HR 0.94, 95% CI 0.70–
1.25; P = 0.67) (Table 3).
The primary endpoint of the composite of all-cause death, rehospi-
talization with MI, cardiogenic shock, or stent thrombosis at 1 year
was consistent across all relevant subgroups (Figure 4).
No patients with STEMI were lost to follow-up for the primary
endpoint.
In-hospital medication, trial and PCI procedures, and complica-
tions, were similar between the treatment groups (oxygen/ambient
air) (Table 2), except for the rate of hypoxaemia (3.2% vs. 13.3%), the
median oxygen saturation at the end of the treatment period (99%
vs. 97%), the rate of unwillingness to continue participation in the trial
(4.1% vs. 0.3%), the rate of clopidogrel use (7.9% vs. 10.7%), and the
use of iv inotropes (2.6% vs. 4.0%), which were significantly different
(P < 0.05).
.. the study
..
.. During the trial period, 7758 STEMI cases were reported at partici-
.. pating sites, and 2807 (36%) were enrolled in the DETO2X trial.
..
.. The remaining 4951 patients not enrolled in the trial were
..
.. followed-up separately. The incidence of the composite of all-cause
.. death, rehospitalization with MI, cardiogenic shock, or stent throm-
..
.. bosis at 1 year (MACE1) was 16.6% (821 of 4951). The incidence of
.. the composite of all-cause death, rehospitalization with MI, cardio-
..
.. genic shock, stent thrombosis, or target vessel revascularization at 1
.. year (MACE2) was 20.0% (988 of 4951). At 1 year, the rate of death
..
.. from any cause was 13.4% (665 of 4951). The rate of rehospitaliza-
.. tion with MI was 3.3% (165 of 4951), the rate of rehospitalization
..
.. with cardiogenic shock was 0.3% (14 of 4951), and the rate of stent
.. thrombosis was 0.7% (35 of 4951) (Table 3).
..
..
..
..
.. Discussion
..
.. In this pre-specified subgroup analysis of the DETO2X trial, an
..
.. investigator-initiated, RRCT of supplemental oxygen or ambient air in
.. patients with STEMI undergoing primary PCI, oxygen therapy did not
..
.. reduce the rate of the composite of all-cause death, rehospitalization
.. with MI, cardiogenic shock, or stent thrombosis at 1 year, at short-
..
. term or the entire follow-up of the trial. Hypoxaemia occurred
Oxygen therapy in STEMI
..
substantially more often in the ambient-air group, but the primary
outcome remained unaffected, most likely due to adequate oxygen
supplementation in these cases. Equally important, we did not find
any signs of increased risk by supplemental oxygen concerning the
primary or secondary endpoints, or any relevant differences in proce-
dures, medication or complications during hospital stay, within 1
year. The neutral outcome was consistent in relevant subgroups re-
gardless of baseline clinical or angiographic characteristics.
As a result of a pragmatic study design, and strong commitment
and compliance of the participating sites, we managed to enrol 36%
of all eligible STEMI cases during the trial period. In less than 3 years,
we were thereby able to enrol six times more STEMI patients than
the largest contemporary oxygen trial.6
Both beneficial and deleterious effects of oxygen therapy in STEMI
patients have been proposed.3–6 The different results may have mul-
tiple explanations. Small clinical trials with hyperbaric3 or supersatu-
rated5 oxygen therapy have showed positive effects on surrogate
endpoints. Other experimental and clinical trials with high doses up
to 100% oxygen by face mask have showed adverse effects. High
doses may lead to hyperoxaemia-related toxic effects.21–23
Preclinical studies suggest a dose-dependent correlation between
oxygen exposure and risk for myocardial injury24 which also was
reported in a post hoc analysis of a recent clinical study.9 The results
of our trial do not refute this potential risk. Our trial used moderate
oxygen doses by open face mask avoiding excessive hyperoxaemia.
To demonstrate dose-dependent toxicity in a clinical trial by using
doses much higher than applied in clinical practice, we perceived as
unethical and impossible to perform.
Further, in experimental studies, haemodynamic, histologic, or bio-
chemical markers were analysed immediately or within short-term in
a small number of subjects.21–23,25 In contrast, our study had long me-
dian follow-up. Haemodynamic changes might be transient with lim-
ited sustained long-term risk. Finally, discrepancies between
preclinical studies26 and smaller clinical trials with surrogate end-
points,3–6 and large clinical trials with hard outcomes are common.
General and conceptual limitations to the main study have been
described in detail previously.14 The results and conclusions of the
present study are drawn from a pre-specified subgroup analysis with-
out formal power and should be considered hypothesis generating.
The lower-than expected event rate in the study population reduces
power for evaluation of the primary endpoint, and we cannot com-
pletely rule out a small beneficial or unfavourable effect of oxygen
treatment. However, the sample studied is large and the data quality
very good concerning the primary objective. We pre-specified a pri-
mary composite endpoint with clinically important outcome variables
relevant for STEMI patients undergoing PCI thus achieving a higher
event rate in order to compensate for a limited sample size. Selected
enrolment of STEMI patients is difficult in this setting as oxygen treat-
ment usually is already started at first medical contact when the diag-
nosis of AMI still is uncertain. Our trial does not have sufficient
power for conclusive subgroup analysis and future research needs to
clarify this aspect.
Although we recruited a large proportion of STEMI cases at partic-
ipating sites, a comparison of the clinical characteristics and outcomes
between the patients who underwent randomization and those who
did not indicate that the two cohorts differed significantly. In general,
patients not participating in the DETO2X trial were older and had a
2739
.. higher incidence of diabetes, MI, and previous PCI treatment. The in-
.. cidence of death, rehospitalization with MI, cardiogenic shock, or
..
.. stent thrombosis within 1 year occurred in 16.6% (821 of 4951) in
.. non-randomized patients, compared to 6.9% (194 of 2807) in the
..
.. study population. These differences most likely reflect the exclusion
.. of frailer patients who were ineligible because they were hypoxaemic
..
.. at presentation or unable for medical reasons to provide oral con-
.. sent, aspects closely linked to poor prognosis.27 Interestingly, other
..
.. endpoints such as rehospitalization for repeat revascularization or
.. stent thrombosis were very similar.
..
.. In the primary analysis of the DETO2X trial, we found that the
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.. broad population of normoxemic patients with suspected acute MI
..
.. does not benefit from routine oxygen supplementation.14 Experts
.. have already called for a change in treatment paradigms towards a
..
.. more restrictive use of supplemental oxygen,28 and the oxygen satur-
.. ation level below which oxygen treatment is recommended has re-
..
.. cently been lowered to 90% in the 2017 European Society of
.. Cardiology guidelines for STEMI patients.29
..
.. We conclude that routine oxygen therapy in normoxemic patients
.. with STEMI did not significantly reduce the rate of the composite of
..
.. all-cause death, reinfarction, cardiogenic shock, or stent thrombosis at 1
..
.. year or longer follow-up. Thus, it appears reasonable and safe to with-
.. hold oxygen therapy in STEMI patients without hypoxaemia at baseline
..
.. which goes well in line with recently changed guidelines.29 Nevertheless,
.. frequent monitoring remains mandatory as a subgroup of patients will
..
.. develop hypoxaemia resulting in a need for immediate oxygen therapy.
..
..
.. Acknowledgements
.. We thank the staffs at all centres participating in the DETO2X col-
..
.. laboration for their professionalism and commitment to this study.
.. We are grateful for the assistance from personnel at Uppsala Clinical
..
.. Research Center, Uppsala University, Uppsala, on all matters of the
..
.. trial.
..
.. Funding
..
.. Swedish Research Council (grant number VR20130307); the Swedish
.. Heart-Lung Foundation (grant numbers HLF20130262, HLF20160688);
..
.. and the Swedish Foundation for Strategic Research (grant number SFF
.. KF10-0024).
..
.. Conflict of interest: Drs Hofmann and Östlund report grants from the
..
.. Swedish Research Council, the Swedish Heart-Lung Foundation, and the
.. Swedish Foundation for Strategic Research. No other potential conflict of
.. interest relevant to this article was reported.
..
..
..
.. References
.. 1. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger
.. MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P,
.. Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S, Baumgartner H,
.. Gaemperli O, Achenbach S, Agewall S, Badimon L, Baigent C, Bueno H,
..
.. Bugiardini R, Carerj S, Casselman F, Cuisset T, Erol C, Fitzsimons D, Halle M,
.. Hamm C, Hildick-Smith D, Huber K, Iliodromitis E, James S, Lewis BS, Lip GY,
.. Piepoli MF, Richter D, Rosemann T, Sechtem U, Steg PG, Vrints C, Luis
.. Zamorano J; ESC Scientific Document Group. 2015 ESC Guidelines for the man-
.. agement of acute coronary syndromes in patients presenting without persistent
.. ST-segment elevation: task Force for the Management of Acute Coronary
.. Syndromes in Patients Presenting without Persistent ST-Segment Elevation of
..
.. 2. the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315.
.. Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, Borger MA, Di Mario C,
.. Dickstein K, Ducrocq G, Fernandez-Aviles F, Gershlick AH, Giannuzzi P,
.. Halvorsen S, Huber K, Juni P, Kastrati A, Knuuti J, Lenzen MJ, Mahaffey KW,
. Valgimigli M, van’t Hof A, Widimsky P, Zahger D, Bax JJ, Baumgartner H, Ceconi
2739a R. Hofmann et al.

C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof

.. Gibbons RJ, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW, Uretsky BF, Gabriel
P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z,  Sechtem U, .. Steg P, Wijns W, Bassand J-P, Menasché P, Ravkilde J, Ohman EM, Antman EM,
..
Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, Hasdai D, Astin F, .. Wallentin LC, Armstrong PW, Simoons ML, Januzzi JL, Nieminen MS, Gheorghiade
Åström-Olsson K, Budaj A, Clemmensen P, Collet J-P, Fox KA, Fuat A, Gustiene .. M, Filippatos G, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D, Smith
O, Hamm CW, Kala P, Lancellotti P, Maggioni AP, Merkely B, Neumann F-J, .. SC, Hu D, Lopez-Sendon J-L, Robertson RM, Weaver D, Tendera M, Bove AA,
Piepoli MF, Van de Werf F, Verheugt F, Wallentin L; Task Force on the manage- .. Parkhomenko AN, Vasilieva EJ, Mendis S, Bax JJ, Baumgartner H, Ceconi C, Dean V,
ment of ST-segment elevation acute myocardial infarction of the European .. Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh
Society of Cardiology (ESC). ESC guidelines for the management of acute myo- .. P, McDonagh T, Moulin C, Popescu BA, Reiner Z,  Sechtem U, Sirnes PA, Tendera M,
cardial infarction in patients presenting with ST-segment elevation. Eur Heart J
.. Torbicki A, Vahanian A, Windecker S, Morais J, Aguiar C, Almahmeed W, Arnar DO,
..
2012;33:2569–2619. .. Barili F, Bloch KD, Bolger AF, Bøtker HE, Bozkurt B, Bugiardini R, Cannon C, de
3. Dekleva M, Neskovic A, Vlahovic A, Putnikovic B, Beleslin B, Ostojic M. .. Lemos J, Eberli FR, Escobar E, Hlatky M, James S, Kern KB, Moliterno DJ, Mueller C,
Adjunctive effect of hyperbaric oxygen treatment after thrombolysis on left ven- .. Neskovic AN, Pieske BM, Schulman SP, Storey RF, Taubert KA, Vranckx P, Wagner
tricular function in patients with acute myocardial infarction. Am Heart J 2004; .. DR; Writing Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal
148:E14. .. Definition of Myocardial Infarction; ESC Committee for Practice Guidelines (CPG).
4. Ukholkina GB, Kostyanov IY, Kuchkina NV, Grendo EP, Gofman YB. Effect of .. Third universal definition of myocardial infarction. Eur Heart J 2012;33:2551–2567.

Downloaded from https://academic.oup.com/eurheartj/article-abstract/39/29/2730/5037999 by guest on 13 August 2019

oxygenotherapy used in combination with reperfusion in patients with acute
.. 20. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG,
..
myocardial infarction. Kardiologiya 2005;45:59–59. .. Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW,
5. Stone GW, Martin JL, de Boer M-J, Margheri M, Bramucci E, Blankenship JC, .. Serruys PW; Academic Research Consortium. Clinical end points in coronary
Metzger DC, Gibbons RJ, Lindsay BS, Weiner BH, Lansky AJ, Krucoff MW, Fahy .. stent trials: a case for standardized definitions. Circulation 2007;115:2344–2351.
M, Boscardin WJ; AMIHOT-II Trial Investigators. Effect of supersaturated oxygen .. 21. McNulty PH, King N, Scott S, Hartman G, McCann J, Kozak M, Chambers CE,
delivery on infarct size after percutaneous coronary intervention in acute myo- .. Demers LM, Sinoway LI. Effects of supplemental oxygen administration on cor-
cardial infarction. Circ Cardiovasc Interv 2009;2:366–325. .. onary blood flow in patients undergoing cardiac catheterization. Am J Physiol
6. Stub D, Smith K, Bernard S, Nehme Z, Stephenson M, Bray JE, Cameron P,
.. Heart Circ Physiol 2005;288:H1057–H1062.
..
Barger B, Ellims AH, Taylor AJ, Meredith IT, Kaye DM; AVOID Investigators. Air .. 22. Momen A, Mascarenhas V, Gahremanpour A, Gao Z, Moradkhan R, Kunselman
versus oxygen in ST-segment-elevation myocardial infarction. Circulation 2015; .. A, Boehmer JP, Sinoway LI, Leuenberger UA. Coronary blood flow responses to
131:2143–2150. .. physiological stress in humans. Am J Physiol Heart Circ Physiol 2009;296:
7. Shuvy M, Atar D, Gabriel Steg P, Halvorsen S, Jolly S, Yusuf S, Lotan C. Oxygen .. H854–H861.
therapy in acute coronary syndrome: are the benefits worth the risk? Eur Heart J .. 23. Bodetoft S, Carlsson M, Arheden H, Ekelund U. Effects of oxygen inhalation on
2013;34:1630–1635. .. cardiac output, coronary blood flow and oxygen delivery in healthy individuals,
8. Moradkhan R, Sinoway LI. Revisiting the role of oxygen therapy in cardiac
.. assessed with MRI. Eur J Emerg Med 2011;18:25–30.
patients. J Am Coll Cardiol 2010;56:1013–1016.
.. 24. Nagato A, Silva FL, Silva AR, Bezerra FS, Oliveira ML, Bello-Klein A, Cristovao
..
9. Nehme Z, Stub D, Bernard S, Stephenson M, Bray JE, Cameron P, Meredith IT, .. Porto L, Santos Valenca S. Hyperoxia-induced lung injury is dose dependent in
Barger B, Ellims AH, Taylor AJ, Kaye DM, Smith K; AVOID Investigators. Effect .. Wistar rats. Exp Lung Res 2009;35:713–728.
of supplemental oxygen exposure on myocardial injury in ST-elevation myocar- .. 25. Waring WS, Thomson AJ, Adwani SH, Rosseel AJ, Potter JF, Webb DJ, Maxwell
dial infarction. Heart 2016;102:444–451. .. SRJ. Cardiovascular effects of acute oxygen administration in healthy adults. J
10. Fordyce CB, Gersh BJ, Stone GW, Granger CB. Novel therapeutics in myocar- .. Cardiovasc Pharmacol 2003;42:245–250.
dial infarction: targeting microvascular dysfunction and reperfusion injury. Trends .. 26. Martic-Kehl MI, Schibli R, Schubiger PA. Can animal data predict human out-
Pharmacol Sci 2015;36:605–616.
.. come? Problems and pitfalls of translational animal research. Eur J Nucl Med Mol
..
11. Zweier JL, Talukder MAH. The role of oxidants and free radicals in reperfusion .. Imaging 2012;39:1492–1496.
injury. Cardiovasc Res 2006;70:181–190. .. 27. Thang ND, Karlson BW, Sundstrom BW, Karlsson T, Herlitz J. Pre-hospital pre-
12. van Werkum JW, Heestermans AA, Zomer AC, Kelder JC, Suttorp MJ, Rensing .. diction of death or cardiovascular complications during hospitalisation and death
BJ, Koolen JJ, Brueren BRG, Dambrink JHE, Hautvast RW, Verheugt FW, ten .. within one year in suspected acute coronary syndrome patients. Int J Cardiol
Berg JM. Predictors of coronary stent thrombosis: the Dutch stent thrombosis .. 2015;185:308–312.
registry. J Am Coll Cardiol 2009;53:1399–1409. .. 28. Loscalzo J. Is oxygen therapy beneficial in acute myocardial infarction? Simple
13. Lagerqvist B, Carlsson J, Frobert O, Lindback J, Schersten F, Stenestrand U,
.. question, complicated mechanism, simple answer. N Engl J Med 2017;377:
..
James SK; Swedish Coronary Angiography; Angioplasty Registry Study Group. .. 1286–1287.
Stent thrombosis in Sweden: a report from the Swedish Coronary Angiography .. 29. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio
and Angioplasty Registry. Circ Cardiovasc Interv 2009;2:401–408. .. ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ,
14. Hofmann R, James SK, Jernberg T, Lindahl B, Erlinge D, Witt N, Arefalk G, Frick .. Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimsky P, Collet J-
M, Alfredsson J, Nilsson L, Ravn-Fischer A, Omerovic E, Kellerth T, Sparv D, .. P, Kristensen SD, Aboyans V, Baumbach A, Bugiardini R, Coman IM, Delgado V,
Ekelund U, Linder R, Ekstrom M, Lauermann J, Haaga U, Pernow J, Ostlund O, .. Fitzsimons D, Gaemperli O, Gershlick AH, Gielen S, Harjola V-P, Katus HA,
Herlitz J, Svensson L; DETO2X–SWEDEHEART Investigators. Oxygen therapy
.. Knuuti J, Kolh P, Leclercq C, Lip GYH, Morais J, Neskovic AN, Neumann F-J,
..
in suspected acute myocardial infarction. N Engl J Med 2017;377:1240–1249. .. Niessner A, Piepoli MF, Richter DJ, Shlyakhto E, Simpson IA, Steg PG, Terkelsen
15. Khoshnood A, Carlsson M, Akbarzadeh M, Bhiladvala P, Roijer A, Nordlund D, .. CJ, Thygesen K, Windecker S, Zamorano JL, Zeymer U, Windecker S, Aboyans
Hoglund P, Zughaft D, Todorova L, Mokhtari A, Arheden H, Erlinge D, Ekelund .. V, Agewall S, Barbato E, Bueno H, Coca A, Collet J-P, Coman IM, Dean V,
U. Effect of oxygen therapy on myocardial salvage in ST elevation myocardial in- .. Delgado V, Fitzsimons D, Gaemperli O, Hindricks G, Iung B, Jüni P, Katus HA,
farction: the randomized SOCCER trial. Eur J Emerg Med 2018;25:78–84. .. Knuuti J, Lancellotti P, Leclercq C, McDonagh T, Piepoli MF, Ponikowski P,
16. Fitterman N. Why oxygen is not necessary for all STEMIs. JAMA Intern Med 2017; .. Richter DJ, Roffi M, Shlyakhto E, Simpson IA, Zamorano JL, Chettibi M,
177:267–268.
.. Hayrapetyan HG, Metzler B, Ibrahimov F, Sujayeva V, Beauloye C, Dizdarevic-
..
17. Jernberg T, Attebring MF, Hambraeus K, Ivert T, James S, Jeppsson A, Lagerqvist .. Hudic L, Karamfiloff K, Skoric B, Antoniades L, Tousek P, Terkelsen PChristian. J,
B, Lindahl B, Stenestrand U, Wallentin L. The Swedish Web-system for .. Shaheen SM, Marandi T, Niemelä M, Kedev S, Gilard M, Aladashvili A, Elsaesser
Enhancement and Development of Evidence-based care in Heart disease .. A, Kanakakis IG, Merkely B, Gudnason T, Iakobishvili Z, Bolognese L,
Evaluated According to Recommended Therapies (SWEDEHEART). Heart 2010; .. Berkinbayev S, Bajraktari G, Beishenkulov M, Zake I, Lamin HB, Gustiene O,
96:1617–1621. .. Pereira B, Xuereb RG, Ztot S, Juliebø V, Legutko J, Timóteo AT, Tatu-Chiţoiu G,
18. Hofmann R, James SK, Svensson L, Witt N, Frick M, Lindahl B, Ostlund O, .. Yakovlev A, Bertelli L, Nedeljkovic M, Studencan M, Bunc M, Garcı́a de Castro
Ekelund U, Erlinge D, Herlitz J, Jernberg T. DETermination of the role of .. AM, Petursson P, Jeger R, Mourali MS, Yildirir A, Parkhomenko A, Gale CP; ESC
OXygen in suspected Acute Myocardial Infarction trial. Am Heart J 2014;167:
.. Scientific Document Group. 2017 ESC Guidelines for the management of acute
..
...
322–328. myocardial infarction in patients presenting with ST-segment elevation: the Task
19. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Thygesen K, Force for the management of acute myocardial infarction in patients presenting
Alpert JS, White HD, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA, Chaitman
.. with ST-segment elevation of the European Society of Cardiology (ESC). Eur
BR, Clemmensen PM, Johanson P, Hod H, Underwood R, Bax JJ, Bonow RO, Pinto F,
.. Heart J 2018;39:119–177.