Articles www.thelancet.com Vol 375 February 27, 2010 727 Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial Hans Erik Bøtker, Rajesh Kharbanda, Michael R Schmidt, Morten Bøttcher, Anne K Kaltoft, Christian J Terkelsen, Kim Munk, Niels H Andersen, Troels M Hansen, Sven Trautner, Jens Flensted Lassen, Evald Høj Christiansen, Lars R Krusell, Steen D Kristensen, Leif Thuesen, Søren S Nielsen, Michael Rehling, Henrik Toft Sørensen, Andrew N Redington, Torsten T Nielsen Summary Background Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage. Methods 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266. Findings 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0·75 (IQR 0·50–0·93, n=73) in the remote conditioning group versus 0·55 (0·35–0·88, n=69) in the control group, with median difference of 0·10 (95% CI 0·01–0·22; p=0·0333); mean salvage index was 0·69 (SD 0·27) versus 0·57 (0·26), with mean difference of 0·12 (95% CI 0·01–0·21; p=0·0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group). Interpretation Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes. Funding Fondation Leducq. Introduction ST-elevation myocardial infarction is a leading cause of mortality and morbidity. Infarct size is an important determinant of outcome. Hence reduction of myocardial injury is a therapeutic mainstay, best achieved by early reperfusion through primary percutaneous coronary intervention. 1 Patients receiving such treatment will achieve infarct-related vessel patency and reperfusion, but risk sustaining clinically significant myocardial infarction, even when the procedure is done soon after symptom onset. 2 Attempts to improve outcomes with adjuvant mechanical treatments such as thrombectomy and distal protection devices show inconsistent benefit. 3–5 An alternative approach for treatment is to exploit innate cytoprotective mechanisms. Findings from recent studies of local postconditioning and targeting of mitochondrial pathways in myocardial infarction have indicated success in reduction of infarct size in patients with occluded left anterior descendent artery. 6,7 Remote ischaemic preconditioning, induced by repeated brief periods of limb ischaemia before index ischaemia, 8 reduces myocardial injury in patients exposed to predictable ischaemia. 9–11 Furthermore, remote ischaemic postconditioning, applied in the early reperfusion phase after prolonged ischaemia, seems to be more effective than local postconditioning in experimental myocardial infarction. 12 We have shown that conditioning, by intermittent limb ischaemia after the onset of myocardial ischaemia and before reperfusion, reduces infarct size in a porcine model. 13 This simple technique can be used during hospital transport. We used myocardial perfusion imaging to examine whether remote ischaemic conditioning done before primary percutaneous coronary intervention increases myocardial salvage, a predictor of mortality, 14 in patients with a first acute and evolving myocardial infarction. Lancet 2010; 375: 727–34 See Comment page 699 Department of Cardiology (Prof H E Bøtker MD, M R Schmidt MD, M Bøttcher MD, A K Kaltoft MD, C J Terkelsen MD, K Munk MD, N H Andersen MD, J F Lassen MD, E H Christiansen MD, L R Krusell MD, S D Kristensen MD, L Thuesen MD, Prof T T Nielsen MD), Department of Nuclear Medicine (S S Nielsen MD, M Rehling MD), and Department of Clinical Epidemiology (Prof H T Sørensen MD), Aarhus University Hospital Skejby, Aarhus N, Denmark; Department of Cardiovascular Medicine, West Wing, John Radcliffe Hospital, Headington, Oxford, UK (R Kharbanda MD); Mobile Emergency Care Unit, Department of Anaesthesiology, Aarhus University Hospital Aarhus, Aarhus C, Denmark (T M Hansen MD); Falck Ambulance Service, The Falck House, Copenhagen, Denmark (S Trautner MD); and Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (Prof A N Redington MD) Correspondence to: Prof Hans Erik Bøtker, Department of Cardiology, Aarhus University Hospital Skejby, DK-8200 Aarhus N, Denmark [email protected]
Transcript
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Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trialHans Erik Bøtker, Rajesh Kharbanda, Michael R Schmidt, Morten Bøttcher, Anne K Kaltoft, Christian J Terkelsen, Kim Munk, Niels H Andersen, Troels M Hansen, Sven Trautner, Jens Flensted Lassen, Evald Høj Christiansen, Lars R Krusell, Steen D Kristensen, Leif Thuesen, Søren S Nielsen, Michael Rehling, Henrik Toft Sørensen, Andrew N Redington, Torsten T Nielsen
SummaryBackground Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage.
Methods 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266.
Findings 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0·75 (IQR 0·50–0·93, n=73) in the remote conditioning group versus 0·55 (0·35–0·88, n=69) in the control group, with median difference of 0·10 (95% CI 0·01–0·22; p=0·0333); mean salvage index was 0·69 (SD 0·27) versus 0·57 (0·26), with mean difference of 0·12 (95% CI 0·01–0·21; p=0·0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group).
Interpretation Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote conditioning on clinical outcomes.
Funding Fondation Leducq.
IntroductionST-elevation myocardial infarction is a leading cause of mortality and morbidity. Infarct size is an important determinant of outcome. Hence reduction of myocardial injury is a therapeutic mainstay, best achieved by early reperfusion through primary percutaneous coronary intervention.1 Patients receiving such treatment will achieve infarct-related vessel patency and reperfusion, but risk sustaining clinically significant myocardial infarction, even when the procedure is done soon after symptom onset.2 Attempts to improve outcomes with adjuvant mechanical treatments such as thrombectomy and distal protection devices show inconsistent benefit.3–5
An alternative approach for treatment is to exploit innate cytoprotective mechanisms. Findings from recent studies of local postconditioning and targeting of mitochondrial pathways in myocardial infarction have indicated success in reduction of infarct size in patients
with occluded left anterior descendent artery.6,7 Remote ischaemic pre conditioning, induced by repeat ed brief periods of limb ischaemia before index ischaemia,8 reduces myocardial injury in patients exposed to predictable ischaemia.9–11 Furthermore, remote ischaemic postconditioning, applied in the early reperfusion phase after prolonged ischaemia, seems to be more effective than local postconditioning in experimental myocardial infarction.12 We have shown that conditioning, by intermittent limb ischaemia after the onset of myocardial ischaemia and before reperfusion, reduces infarct size in a porcine model.13 This simple technique can be used during hospital transport.
We used myocardial perfusion imaging to examine whether remote ischaemic conditioning done before primary percutaneous coronary intervention increases myocardial salvage, a predictor of mortality,14 in patients with a first acute and evolving myocardial infarction.
Lancet 2010; 375: 727–34
See Comment page 699
Department of Cardiology (Prof H E Bøtker MD, M R Schmidt MD, M Bøttcher MD, A K Kaltoft MD, C J Terkelsen MD, K Munk MD, N H Andersen MD, J F Lassen MD, E H Christiansen MD, L R Krusell MD, S D Kristensen MD, L Thuesen MD, Prof T T Nielsen MD), Department of Nuclear Medicine (S S Nielsen MD, M Rehling MD), and Department of Clinical Epidemiology (Prof H T Sørensen MD), Aarhus University Hospital Skejby, Aarhus N, Denmark; Department of Cardiovascular Medicine, West Wing, John Radcliffe Hospital, Headington, Oxford, UK (R Kharbanda MD); Mobile Emergency Care Unit, Department of Anaesthesiology, Aarhus University Hospital Aarhus, Aarhus C, Denmark (T M Hansen MD); Falck Ambulance Service, The Falck House, Copenhagen, Denmark (S Trautner MD); and Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (Prof A N Redington MD)
Correspondence to: Prof Hans Erik Bøtker, Department of Cardiology, Aarhus University Hospital Skejby, DK-8200 Aarhus N, Denmark [email protected]
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MethodsPatientsThis prospective, single-centre randomised controlled trial was done during February, 2007–November, 2008 in Aarhus University Hospital Skejby, Aarhus N, Denmark. Eligible patients were aged 18 years or older; presented with chest pain before admission to hospital and within 12 h of onset; had ST-segment elevation of more than 0·1 mV in two contiguous leads in the first electro-cardiogram (ECG) recorded on the scene; and were telemedically assigned the clinical decision to receive primary percutaneous coronary intervention on hospital arrival. Exclusion criteria were: left bundle branch block; previous myocardial infarction; fibrinolytic treatment in the previous 30 days; previous coronary bypass surgery; left main stem stenosis requiring coronary bypass surgery; or severe heart failure requiring mechanical ventilation or use of an intra-aortic balloon pump. Patients who did not meet inclusion criteria were excluded either immediately on arrival at hospital or when biochemical ischaemic markers failed to confirm the diagnosis of myocardial infarction. The study protocol was approved by the regional ethics committee and was done in accordance with the
Helsinki II declaration. Informed consent was obtained in the ambulance by the paramedic or emergency physician.
Randomisation and maskingComputer-generated block randomisation with varying block sizes (6, 4, or 2) was used to randomly assign consecutive patients in a 1:1 ratio (single-blind) to treatment: standard primary percuta neous coronary intervention (control group), or standard primary percutaneous coronary intervention plus remote conditioning through intermittent arm ischaemia (four cycles of alternating 5-min inflation and 5-min deflation of a standard upper-arm blood-pressure cuff to 200 mm Hg; intervention group). The randomisation sequence was generated by an independent organisation (Cervus Results, DK-Aarhus, Denmark). By telephone confirmation with the on-call physician at the intervention centre, sealed, numbered, opaque envelopes containing the study group assignments were opened for consecutive patients, and every patient’s allocated treatment was communicated to ambulance personnel. Individuals doing remote conditioning and primary percutaneous coronary intervention were not masked to treatment assignment, but none of them participated in the data analysis. Individuals participating in data analysis were masked to treatment assignment, but success of masking was not assessed.
ProceduresRemote conditioning was started by ambulance personnel during transport. For 16 patients, transportation time was insufficient for four cycles of inflation and deflation, so the procedure continued in hospital during primary percutaneous coronary intervention and was completed before reperfusion. Before coronary intervention, all patients were treated with 300 mg aspirin orally or intravenously, 600 mg clopidogrel orally, and 10 000 IU unfractionated heparin intravenously. During coronary intervention, patients were treated with abciximab unless contraindicated. After intervention, patients received infusion of abciximab for 12 h, lifelong 75 mg aspirin daily, and 75 mg clopidogrel daily for 12 months.
The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, estimated by gated single photon emission CT (SPECT).14 Before reperfusion therapy was started, patients received 700 MBq (±10%) Technetium-sestamibi intravenously to quantify area at risk of infarction. SPECT was done with a high-resolution parallel-hole collimator dual-headed rotating gamma camera (ADAC Laboratories, Forte, Milpitas, CA, USA) within 8 h of injection of the radionuclide: median 196 min (IQR 148–321) in the control group, and 200 min (165–342) in the remote conditioning group (p=0·50). An identical protocol was used to quantify final infarct size 30 days after primary percutaneous coronary intervention, but imaging was
333 patients assessed for eligibility and randomly assigned to treatment
166 received standard primary percutaneous coronary intervention plus remote conditioning (intervention group)
126 eligible for inclusion in data analysis (intention-to-treat analysis)
125 eligible for inclusion in data analysis (intention-to-treat analysis) 76 had area-at-risk data
40 excluded on arrival at hospitalbecause did not meetstudy criteria15 ST-elevation myocardial
infarction not confirmed1 previous coronary artery
bypass graft3 onset of chest pain
>12 h before21 previous myocardial
infarction
42 excluded on arrival at hospitalbecause did not meetstudy criteria19 ST-elevation myocardial
infarction not confirmed3 previous coronary artery
bypass graft20 previous myocardial
infarction
167 received standard primary percutaneous coronary intervention (control group)
Figure 1: Trial profile
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started 60 min after tracer injection. To ensure equal count statistics, acquisition time varied between 25 s and 60 s per projection, dependent on the time elapsed since tracer injection. Images were gated at eight frames per cardiac cycle with no scatter or attenuation correction.
Imaging data were analysed independently by two experienced nuclear cardiology readers who were masked to treatment assignment and clinical data. Images were analysed with the commercially available automatic program Quantitative Perfusion SPECT (Cedars-Sinai Medical Center, Los Angeles, CA, USA).2 In case of failure of the automatic quantification algorithm, methods to mask extracardiac activity or to define the valve plane and apex of the left ventricle, or both, were used. Final infarct size and area at risk were calculated as the area of the left ventricle containing counts lower than a mean normal limit for pixels according to the MIBIMIBI rest database.2 If the difference in defect size between the cardiology readers exceeded 3%, a consensus reading was obtained from the two readers. In patients with data for area at risk and final infarct size, the amount of myocardial salvage was calculated as the difference between area at risk and final infarct size, expressed as a percentage of the left ventricular mass volume. Salvage index was calculated as: (area at risk–final infarct size)/area at risk. Prespecified subgroups for the primary outcome only were vessel patency before primary percutaneous coronary intervention and infarct location.
Secondary endpoints were: final infarct size at 30 days after primary percutaneous coronary intervention; troponin-T concentrations; markers of reperfusion from corrected thrombolysis in myocardial infarction (TIMI) frame count and ST-segment resolution; death; reinfarction; hospital admission within 30 days of the intervention for heart failure; and left ventricular ejection fraction and New York Heart Association (NYHA) class of disease at 30 days. Troponin-T concentrations were measured on arrival at hospital, and at 8–12 h, 20–24 h, and 90–102 h after symptom onset.
Coronary angiographic measurements were made immediately before revascularisation with standard tech-niques. Two experienced individuals, masked to treat ment assignment and clinical data, made all measurements and analysed angiography data. Angiographic TIMI flow grade was visually estimated, and the corrected TIMI frame count was measured immediately after primary per-cutaneous coronary intervention.15
Patients were monitored with a 12-lead ST-monitoring ECG (LIFEPAK 12, Medtronic Emergency Response Systems, Minneapolis, MN, USA) from arrival of the ambulance at the scene and throughout transport. The analogue ECG signals were digitised for processing with the 12SL ECG interpretive algorithm by GE Marquette Medical Systems (Freiburg, Germany). These data were analysed by individuals masked to treatment assignment and clinical data in our electrocardiographic core laboratory.16 ECG data recorded before primary per-
cutaneous coronary intervention was used as the baseline measurement to detect whether 70% or more ST-segment resolution was achieved within 90 min of first wire.
Echocardiography was done and analysed within 30 h of primary percutaneous coronary intervention, and repeated 30 days after intervention by individuals who were masked to all clinical and angiographic data and to treatment assignment, with a commercially available ultrasound system (Vivid 7, GE Healthcare, Horten, Norway) and a 3·5 MHz phased array transducer (M4S, GE Healthcare, Horten, Norway). Left ventricular ejection fraction was assessed from the wall-motion
Stenting of culprit lesion by pPCI 115 (91%) 115 (92%) 22 (55%) 24 (57%)
TIMI flow grade after procedure
0 2 (2%) 3 (2%) 2 (5%) 2 (5%)
I 3 (2%) 2 (2%) 3 (8%) 0
II 9 (7%) 10 (8%) 1 (3%) 2 (5%)
III 112 (89%) 110 (88%) 34 (85%) 38 (90%)
Drug given at time of pPCI
Heparin 126 (100%) 125 (100%) 24 (60%) 22 (52%)
Aspirin 122 (97%) 120 (96%) 40 (100%) 41 (98%)
Clopidogrel 120 (95%) 121 (97%) 36 (90%) 39 (93%)
Abciximab 104 (83%) 109 (87%) 24 (60%) 22 (52%)
Data are mean (SD), number (%), or median (IQR). pPCI= primary percutaneous coronary intervention. TIMI=thrombolysis in myocardial infarction.
Table 1: Baseline characteristics and procedural data for all patients
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score index, calculated as the mean segmental score (3 hyperkinetic, 2 normal, 1 hypokinetic, 0 akinetic, –1 dyskinetic) from 16 myocardial segments.17
Statistical analysisPrevious studies of primary percutaneous coronary intervention have shown the area at risk to be 30% and final infarct size to be 15% of the left ventricle;18 a reduction in infarct size from 20% to 12% is associated with lowered mortality.19,20 We powered the study to detect an increase in the mean salvage index from 0·50 to 0·60. With the assumption that the SD of the salvage index was 0·23,3 we calculated that with 80% power and α=0·05 (two-sided), 109 patients were needed per treat ment group. Our recruitment target was 250 patients.
Three types of analysis were done: 1) analysis of all patients who were assessed for the trial and randomly allocated to treatment in the ambulance; 2) intention-to-treat analysis of patients fulfilling study entry criteria; and 3) per-protocol analysis of patients who completed follow-up with data for myocardial salvage index and final infarct size. We assessed whether the distribution of the main clinical variables was similar between patients randomly allocated to the intervention versus
the control group, taking into account whether they later fulfilled eligibility criteria. To examine possible bias due to exclusion after random isation of patients without verified infarct,21 and possible effect of the intervention on the diagnosis itself, we compared baseline and procedural characteristics, and secondary endpoints available in patients included in the analysis versus those who were excluded. Similarly, to examine whether missing imaging data introduced selection bias, we compared baseline and procedural characteristics and secondary endpoints between included patients and patients lost to follow-up.
Variables conforming to normal distribution were summarised as means (SD) and otherwise as median counts (IQR). We used the t test or Mann-Whitney U test to compare continuous variables, and χ² test or Fisher’s exact test to compare categorical variables. Release of troponin T was compared between the two treatment groups with a multivariate repeated-measurement method and log-transformed values. For the regression lines of plotted final infarct size against area at risk, we assumed proportionality in each treatment group. Slopes of the regression lines were estimated with linear regression. Because of increasing
pPCI plus remote conditioning pPCI p value
Patients Median (IQR) Patients Median (IQR)
Overall population
Salvage index 73 0·75 (0·50–0·93) 69 0·55 (0·35–0·88) 0·0333
Area at risk (% of left ventricle) 73 26% (20–40) 69 28% (22–42) 0·97
Salvage (% of left ventricle) 73 16% (10–25) 69 12% (5–23) 0·0368
Final infarct size (% of left ventricle) 109 4% (1–14) 110 7% (1–21) 0·10
Vessel patency before procedure*
Occluded (TIMI flow grade 0–I)
Salvage index 43 0·74 (0·47–0·87) 42 0·53 (0·35–0·71) 0·0313
Area at risk (% of left ventricle) 43 33% (23–44) 42 34% (24–44) 0·65
Final infarct size (% of left ventricle) 64 9% (3–17) 69 13% (4–24) 0·06
Not occluded (TIMI flow grade II–III)
Salvage index 30 0·78 (0·50–1·00) 27 0·86 (0·31–1·00) 0·71
Area at risk (% of left ventricle) 30 16% (12–20) 27 16% (10–22) 0·98
Final infarct size (% of left ventricle) 45 1% (0–7) 41 1% (0–5) 0·62
Infarct location†
Left anterior descending artery
Salvage index 29 0·78 (0·47–0·93) 29 0·51 (0·38–0·69) 0·06
Area at risk (% of left ventricle) 29 35% (27–41) 29 38% (26–46) 0·72
Final infarct size (% of left ventricle) 43 8% (1–17) 44 16% (4–25) 0·0108
Not left anterior descending artery
Salvage index 44 0·74 (0·52–0·95) 40 0·67 (0·30–0·96) 0·27
Area at risk (% of left ventricle) 44 22% (13–35) 40 23% (8–33) 0·78
Final infarct size (% of left ventricle) 66 4% (1–13) 66 4% (1–12) 0·94
TIMI=thrombolysis in myocardial infarction. *For interaction of vessel patency before procedure with remote conditioning, p=0·96 for area at risk, p=0·15 for salvage index, and p=0·35 for final infarct size. †For interaction of infarct location with remote conditioning, p=0·99 for area at risk, p=0·86 for salvage index, and p=0·13 for final infarct size.
Table 2: Salvage, area at risk, and final infarct size, according to vessel patency before primary percutaneous coronary intervention (pPCI), with or without remote conditioning, and infarct location (per-protocol analysis)
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variance, the CIs were bootstrapped. The p value for the difference in slopes corresponds to the probability of a more extreme difference in slopes based on a permutation. Interaction analysis was done with multivariable regression analysis. Statistical analyses were done with Stata/IC (version 10.1).
This study is registered with ClinicalTrials.gov, number NCT00435266.
Role of the funding sourceThe sponsor had no role in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.
ResultsFigure 1 shows the trial profile. 333 patients were assessed during ambulance transport and randomly allocated to treatment, but 82 patients did not fulfil entry criteria on arrival at the hospital and were excluded. Of the remaining 251 patients, final infarct size was obtained in 110 (88%) patients in the control group and 109 (87%) in the intervention group. A lack of 24-h imaging availability meant that acute myocardial perfusion imaging was not possible in all patients within 8 h after primary percutaneous coronary intervention, so paired scans to calculate salvage index were obtained in 69 (55%) patients in the control group and 73 (58%) in the remote conditioning group; these patients formed the study population for the per-protocol analysis. Median follow-up time was 34 days (IQR 31–42) in the control group and 35 days (30–41) in the remote conditioning group (p=0·66).
For 251 patients who were included in the study, medically treated hypertension was more prevalent in the intervention group than in the control group; other baseline characteristics were similar between the two groups (table 1). Symptom-to-balloon time and TIMI flow grade at admission were similar between the groups; TIMI flow grade III after primary percutaneous coronary intervention was achieved with the same frequency in both groups.
In the first analysis of all patients assessed for eligibility and randomised (n=333 patients), for those that had available data, the median salvage index in the intervention group (0·69, IQR 0·44–0·93, n=80) was not significantly higher than in the control group (0·54, 0·31–0·86, n=78; p=0·13). Similarly, median area at risk was 26% of left ventricle (IQR 23–29, n=100) in the remote conditioning group, compared with 24% (20–27, n=97) in the control group (p=0·15). However, salvage as a percentage of left ventricle was significantly higher in the intervention group (16%, 8–24, n=82) than in the control group (11%, 3–22, n=83; p=0·0391). Differences were not significant between the remote conditioning
group and control group for: final infarct size (median 7% of left ventricle, IQR 1–20 for both groups; p=0·94); left ventricular ejection fraction at admission (median 45%, IQR 35–53 vs 45%, 36–53; p=0·57) and after 30 days (53%, 45–58 vs 51%, 43–58; p=0·43); peak troponin-T release (median 3·12 µg/L, IQR 0·76–7·08 vs 3·72 µg/L, 1·05–7·41; p=0·26); troponin-T release 90–102 h after angioplasty (median 1·46 µg/L, IQR 0·43–3·84 vs 2·90 µg/L, 1·43–5·49; p=0·15); corrected TIMI frame count (median 15, IQR 9–24 vs 15, 9–25; p=0·60); the proportion of patients achieving 70% ST-segment resolution within 90 min after primary percutaneous coronary intervention (106/146, 73% vs 104/142, 73%; p=0·90); or NYHA class of disease at 30 days (p=0·75). No local adverse effects (eg, pain, thrombophlebitis) were recorded.
82 patients were excluded from the study on arrival at hospital because the diagnosis of myocardial infarction could not be confirmed (n=34), or the patient had had previous coronary artery bypass graft (n=4), onset of chest pain 12 h earlier or more (n=3), or previous myocardial infarction (n=41; figure 1). Between the control and intervention groups, no difference was recorded in the proportion of patients excluded because diagnosis of acute myocardial infarction could not be confirmed (p=0·13). Excluded control (n=42) and intervention (n=40) patients had similar mean ages (p=0·74), proportion of men (p=0·14), and distribution of risk factors (p=0·52) or presence of infarct-related artery (p=0·98; table 1). Symptom-to-balloon time did not differ between the 23 patients in the control group and 25 in the intervention group undergoing angioplasty but excluded from imaging analysis because of previous myocardial infarction, previous coronary artery bypass graft, or symptom onset 12 h or more before balloon inflation (p=0·49). TIMI flow grade was similar before
Figure 2: Relation between final infarct size and area at risk for patients receiving primary percutaneous coronary intervention with or without remote conditioning (per-protocol analysis)
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(p=0·67) and after (p=0·17) primary percutaneous coronary interven tion for all 82 excluded patients in the control and intervention groups.
For the 48 patients excluded because of previous myocardial infarction, previous coronary artery bypass graft, or symptom onset 12 h or more before balloon inflation, plasma troponin-T concentration was raised at hospital admission, but 90–102 h after symptom onset, concentrations did not differ between groups (median 2·81 µg/L, IQR 0·99–4·7 for control group vs 1·70 µg/L, 0·35–3·89 for intervention group; p=0·44). Two further patients (one from each group) had pericarditis and were excluded; therefore, for the 50 excluded patients with ST-segment elevation, 22% (5/23) of the control group and 26% (7/27) of the intervention group failed to achieve 70% ST-segment resolution 90 min after primary percutaneous coronary intervention (p=0·48). For the included and excluded patient populations, patients with and without available data on myocardial perfusion did not differ in terms of baseline characteristics (table 1), or, after the procedure, in results for troponin-T release, ST-segment resolution, left ventricular ejection fraction, and NYHA class of disease.
In the per-protocol analysis, the primary endpoint of salvage index was significantly higher in the remote conditioning group than in the control group: mean 0·69 (SD 0·27) versus 0·57 (0·26) with mean difference of 0·12 (95% CI 0·01–0·21, p=0·0333); median difference 0·10 (95% CI 0·01–0·22; table 2). Area at risk did not differ between the two groups (table 2). Percentage salvage was greater in the intervention group than in the control group; final infarct size was lower but the difference was
not significant (mean 8% of left ventricle, SD 10 vs 12%, 13; p=0·10; table 2). A significant positive correlation was recorded between area at risk and final infarct size in both the control (r²= 0·34, 95% CI 0·16–0·52, p<0·0001) and intervention (r²=0·36, 0·16–0·52, p<0·0001) groups (figure 2). In the remote conditioning group the slope of the regression line (0·34, 95% CI 0·27–0·41) was lower than in the control group (0·48, 0·41–0·55; difference 0·14, 95% CI 0·04–0·24, p=0·0080), suggesting that for a given area at risk, smaller infarcts developed in the intervention group.
In the per-protocol analysis of the primary endpoint in patient subgroups, independent of remote conditioning, area at risk was higher in patients with occluded arteries on admission (p=0·0095) and patients with infarctions of the left anterior descendent artery (p=0·0115; table 2). Similarly, salvage index was higher in patients with an open vessel at admission than in those with an occluded artery (p=0·0211). Remote conditioning was associated with a higher myocardial salvage index in patients with an occluded artery on admission than in the control group; it also increased salvage in patients with infarctions of the left anterior descendent artery, although the difference was not significant, and it significantly reduced final infarct size (table 2). However, the interaction of remote conditioning with vessel occlusion or infarct location was not significant for increase in salvage index.
In the intention-to-treat analysis, assessment of the secondary endpoint of plasma troponin-T concentra-tions showed no difference between the groups in peak median values: 3·83 µg/L (IQR 1·28–8·42) for control group versus 3·86 µg/L (1·36–7·40) for intervention group (p=0·80). 90–102 h after symptom onset, troponin-T concentrations tended to be lower in the remote conditioning group than in the control group (median 1·66 µg/L, IQR 0·83–3·84 vs 3·30 µg/L, 1·64–5·49; p=0·06). The study groups did not differ according to the proportion of patients achieving 70% ST-segment resolution within 90 min of primary percutaneous coronary intervention: 84/117 (72%) in the control group versus 91/121 (75%) in the remote conditioning group (p=0·55). Corrected median TIMI frame count was unaffected by the intervention: 15 (IQR 9–25) in the control group versus 15 (9–21) in the remote conditioning group (p=0·64). Within 24 h of primary percutaneous coronary intervention, we recorded an increased left ventricular ejection fraction in patients receiving remote conditioning, including those with an occluded vessel at admission and an infarct of the left anterior descendent artery (table 3). However, at 30 days, left ventricular ejection fraction was not significantly different between the groups, and we recorded no differences in major adverse coronary events (in each group, three patients died, one had reinfarction, and three developed heart failure; p=1·0) or in NYHA class (p=0·75).
pPCI plus remote conditioning
pPCI p value
Patients Left ventricular ejection fraction
Patients Left ventricular ejection fraction
Within 24 h after pPCI
All 120 47% (39–54) 116 43% (36–51) 0·0223
Occluded at admission* 53 45% (41–53) 60 42% (36–49) 0·0346
Not occluded at admission† 67 47% (39–56) 56 47% (41–53) 0·49
Not left anterior descending artery 66 53% (47–58) 64 55% (49–58) 0·39
Data are number or median (IQR). Data were analysed by intention to treat, but data were not available for some patients within 24 h after pPCI (n=9 patients receiving pPCI, n=6 receiving pPCI plus remote conditioning) and 30 days after pPCI (n=19, n=20). *Thrombosis in myocardial infarction (TIMI) flow grade 0–I. †TIMI flow grade II–III.
Table 3: Left ventricular ejection fraction estimated by echocardiography 24 h and 30 days after primary percutaneous coronary intervention (pPCI), with or without remote conditioning (intention-to-treat analysis)
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DiscussionOur study shows that remote ischaemic conditioning, induced by intermittent upper-arm ischaemia and done before primary percutaneous coronary intervention, can attenuate reperfusion injury in patients with evolving myocardial infarction, thereby resulting in increased myocardial salvage. This protective effect seemed to be strongest in patients with totally occluded vessels and with infarcts in the left anterior descending artery—both of which were associated with almost double the area at risk—but we did not record an interaction of remote conditioning with occluded vessels or infarct location.
The protective effect of remote conditioning seemed to increase with increasing area at risk, independently of artery occlusion and infarct location. However, infarct size shrinks during the 30 days between quantification of area at risk and final infarct size. Therefore, the amount of shrinkage might be more noticeable in large than in small infarcts, so myocardial salvage due to remote conditioning could be underestimated in patients with smaller infarcts. Since the safety profile of remote conditioning is favourable, no patient should be denied this treatment.
Our results are consistent with other studies examining myocardial salvage. We restricted our analysis to patients with a first myocardial infarction because SPECT allows no distinction between previous and new infarcts. One MRI scan alone might be able to accurately assess area at risk and final infarct size,24 but this technique remains to be validated for quantification.25 In our study, remote conditioning was associated with a substantially lower mean final infarct size than in the control group, comparing favourably with the amount of protection from postconditioning6 and ciclosporin.7 Final infarct size was smaller than in previous studies in which quantitative imaging was used as the endpoint.18 This finding is indicative of the well established and effective treatment of ST-elevation myocardial infarction at present,3,26 and remote conditioning can also confer additional benefit over best medical practice procedures that are presently in use.
In previous studies, investigators have focused on aggressive antiplatelet or mechanical interventions that aim to achieve superior vessel patency. Our study extends into the novel concept of cytoprotection therapy in acute infarction. We did not detect any differences between study groups in vessel patency either before or after primary percutaneous coronary intervention, suggesting that attenuation of reperfusion injury occurs within cells. Cytoprotection could therefore add to the benefits achieved by reperfusion alone. Mechanisms underlying such benefits could be associated with effects on mitochondria,27 circulating inflammatory cells,28 or transcriptional upregulation of protective pathways.29,30
Our study adds to positive data from clinical post-conditioning and cyclosporine intervention studies and
suggests that targeting of cellular protection, in addition to restoration of perfusion, could improve outcomes.6,7 Unlike postconditioning, remote conditioning is not limited to patients undergoing mechanical reperfusion. By contrast with many interventions recently tested in the context of primary angioplasty,4–6 remote conditioning can be applied as an adjunct to pharmacological reperfusion—eg, situations in which emergency primary percutaneous coronary intervention is unavailable, or in other ischaemia-reperfusion syndromes treated with thrombolytics, such as stroke. Moreover, treatment can be started during transport to hospital.
None of the reperfusion endpoints that was calculated independently of imaging differed between the study groups. Because imaging was not always available on a 24-h basis, data for endpoints calculated without imaging data were obtained for more patients than for endpoints that required paired myocardial perfusion imaging (ie, myocardial salvage index). No differences were recorded in the proportion of patients excluded after randomisation because the diagnosis of myocardial infarction could not be confirmed, and the characteristics of dropouts and those who adhered to study protocol were similar, both of which suggest that substantial selection bias did not occur. However, biochemical ischaemia markers, ST-segment resolution, and corrected TIMI frame count might not be sufficiently sensitive to detect differences in a moderately sized study population.3 Subgroup analysis of the primary endpoint by infarct location and vessel patency before procedure, and analyses of secondary endpoints were not sufficiently powered to detect significant differences.
The effectiveness of remote conditioning after onset of target-organ ischaemia could have implications for myocardial infarction and stroke treated with thrombolytics. Moreover, the inter vention’s simplicity, low cost, and effectiveness make it attractive for testing in large-scale clinical trials.ContributorsAll authors contributed to report writing, trial design, and the review of published work. HEB wrote the study protocol; contributed to conceptual design, recruitment and enrolment of patients, follow-up of patients, data quality control, and angiographic and general data analysis; and drafted the report and figures. TTN, RK, MRS, and ANR contributed to conceptual design and data analysis. MB contributed to angiographic data analysis, and recruitment and enrolment of patients. KM and NHA did echocardiography studies and data analysis, and KM contributed to statistical analysis. AKK, SSN, and MR did scintigraphy and data analysis. CJT did electrocardiography analysis. TMR and ST organised patient enrolment in the Mobile Emergency Care Unit. HTS contributed to data and statistical analysis, and revision of the paper. JFL, EHC, LRK, SDK, and LT contributed to recruitment and enrolment of patients.
Conflicts of interestWe declare that we have no conflicts of interest.
AcknowledgmentsThe study was funded by a grant from Fondation Leducq (grant number 06CVD). RK was funded by the Oxford Biomedical Research Centre. We thank Mette Toftdal; paramedics and emergency physicians for study implementation before hospital admission; nurses Karrina Clausen and
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Anne Christine Christensen; secretaries Birgitte Monefeldt and Hanne Kjeldahl Schlosser; and the staff of the catheterisation laboratory, coronary care unit, and Department of Nuclear Medicine in Aarhus University Hospital Skejby, Denmark, for their enthusiastic support.
References1 Andersen HR, Nielsen TT, Rasmussen K, et al, for the DANAMI-2
Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003; 349: 733–42.
2 Kaltoft A, Nielsen SS, Terkelsen CJ, et al. Scintigraphic evaluation of routine filterwire distal protection in percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: a randomized controlled trial. J Nucl Cardiol 2009; 16: 784–91.
3 Kaltoft A, Bottcher M, Nielsen SS, et al. Routine thrombectomy in percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction: a randomized, controlled trial. Circulation 2006; 114: 40–7.
4 Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med 2008; 358: 557–67.
5 Sardella G, Mancone M, Bucciarelli-Ducci C, et al. Thrombus aspiration during primary percutaneous coronary intervention improves myocardial reperfusion and reduces infarct size: the EXPIRA (thrombectomy with export catheter in infarct-related artery during primary percutaneous coronary intervention) prospective, randomized trial. J Am Coll Cardiol 2009; 53: 309–15.
6 Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005; 112: 2143–48.
7 Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008; 359: 473–81.
8 Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation 2002; 106: 2881–83.
9 Cheung MM, Kharbanda RK, Konstantinov IE, et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 2006; 47: 2277–82.
10 Kharbanda RK, Li J, Konstantinov IE, et al. Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study. Heart 2006; 92: 1506–11.
11 Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 2007; 370: 575–79.
12 Gritsopoulos G, Iliodromitis EK, Zoga A, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits. Cardiovasc Drugs Ther 2009; 23: 193–98.
13 Schmidt MR, Smerup M, Konstantinov IE, et al. Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic preconditioning. Am J Physiol Heart Circ Physiol 2007; 292: H1883–90.
14 Ndrepepa G, Mehilli J, Schwaiger M, et al. Prognostic value of myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. J Nucl Med 2004; 45: 725–29.
15 Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count. A quantitative method of assessing coronary artery flow. Circulation 1996; 93: 879–88.
16 Terkelsen CJ, Norgaard BL, Lassen JF, et al. Potential significance of spontaneous and interventional ST-changes in patients transferred for primary percutaneous coronary intervention: observations from the ST-MONitoring in Acute Myocardial Infarction study (The MONAMI study). Eur Heart J 2006; 27: 267–75.
17 Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two–dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989; 2: 358–67.
18 Kastrati A, Mehilli J, Dirschinger J, et al, for the Stent versus Thrombolysis for Occluded Coronary Arteries in Patients With Acute Myocardial Infarction (STOPAMI-2) Study Investigators. Myocardial salvage after coronary stenting plus abciximab versus fibrinolysis plus abciximab in patients with acute myocardial infarction: a randomised trial. Lancet 2002; 359: 920–25.
19 Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial infarction measured by quantitative tomographic mTc sestamibi imaging predicts subsequent mortality. Circulation 1995; 92: 334–41.
20 Burns RJ, Gibbons RJ, Yi Q, et al. The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol 2002; 39: 30–36.
21 Fletcher RH, Fletcher SW. Clinical epidemiology: the essentials, 4th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2005.
22 Chia S, Senatore F, Raffel OC, Lee H, Wackers FJ, Jang IK. Utility of cardiac biomarkers in predicting infarct size, left ventricular function, and clinical outcome after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2008; 1: 415–23.
23 Bohmer E, Hoffmann P, Abdelnoor M, Seljeflot I, Halvorsen S. Troponin T concentration 3 days after acute ST-elevation myocardial infarction predicts infarct size and cardiac function at 3 months. Cardiology 2009; 113: 207–12.
24 Aletras AH, Tilak GS, Natanzon A, et al. Retrospective determination of the area at risk for reperfused acute myocardial infarction with T2-weighted cardiac magnetic resonance imaging: histopathological and displacement encoding with stimulated echoes (DENSE) functional validations. Circulation 2006; 113: 1865–70.
25 Carlsson M, Ubachs JF, Hedstrom E, Heiberg E, Jovinge S, Arheden H. Myocardium at risk after acute infarction in humans on cardiac magnetic resonance: quantitative assessment during follow-up and validation with single-photon emission computed tomography. JACC Cardiovasc Imaging 2009; 2: 569–76.
26 Terkelsen CJ, Lassen JF, Norgaard BL, et al. Reduction of treatment delay in patients with ST-elevation myocardial infarction: impact of pre-hospital diagnosis and direct referral to primary percutanous coronary intervention. Eur Heart J 2005; 26: 770–7.
27 Wang L, Oka N, Tropak M, et al. Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg 2008; 136: 335–42.
28 Konstantinov IE, Arab S, Kharbanda RK, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 2004; 19: 143–50.
29 Kristiansen SB, Henning O, Kharbanda RK, et al. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism. Am J Physiol Heart Circ Physiol 2005; 288: H1252–56.
30 Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol 2005; 288: H971–76.
Comment
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See Articles page 727
Giving the ischaemic heart a shot in the armDespite the progress made, acute myocardial infarction remains a major threat to health worldwide. Although reperfusion therapy improves the prognosis of patients with acute myocardial infarction, reperfusion can also irreversibly damage part of the previously ischaemic myocardium, and thereby attenuate the expected benefit: so-called lethal reperfusion injury. Repeated cycles of brief ischaemia and reperfusion either before extended ischaemia (preconditioning) or within the first minute of reflow (postconditioning) can protect from this lethal reperfusion injury and reduce infarct size by 30–70% in animal models.1,2 In clinical settings, recent small proof-of-concept studies showed that ischaemic postconditioning substantially reduces infarct size, and emphasised that lethal reperfusion injury represents a large amount of the overall myocardial damage after acute myocardial infarction and that this tissue destruction can be prevented by a timely intervention.3,4
Experimental evidence further indicates that transient ischaemia of a wide range of tissues can induce a systemic effect with remote protection of the heart (or the brain) against a simultaneous or subsequent prolonged ischaemia-reperfusion injury.5,6 In The Lancet today, Hans Bøtker and colleagues7 report a randomised study in which arm ischaemia (induced by four cycles of alternating 5-min inflation and 5-min deflation of a standard upper-arm blood-pressure cuff) significantly increased myocardial salvage in 142 patients with ST-elevation acute myocardial infarction (STEMI). The patients were having a first acute myocardial infarction, and all had primary percutaneous coronary intervention on arrival at hospital. The intervention group started arm ischaemia during transport to hospital. The primary endpoint was a myocardial salvage index.
Because infarct size is a determinant of adverse left-ventricular remodelling, heart failure, and mortality after myocardial infarction, its reduction seems the best-suited strategy for the treatment of acute myocardial infarction.8,9 Besides transferring remote conditioning to a real clinical setting, Bøtker and colleagues should be congratulated for taking into consideration several major confounders that are known to influence the results of all studies of reductions in infarct size.
These investigators first considered the timing of the therapeutic intervention with respect to the time of
reopening of the occluded coronary artery. In their study design, about 40% of patients had a patent coronary artery at admission, which indicates that at least for some patients the protective arm ischaemia was applied beyond the recommended time-window,10 after the first minute of reflow, which probably lowered the expected benefit of the protective intervention. Indeed, when they analysed the subgroup of patients with a fully occluded coronary artery at admission, they found much higher myocardial salvage.
Assessment of area at risk size, the major determinant of infarct size, remains an unresolved issue in the clinical settings of STEMI, and again Bøtker and colleagues should be congratulated for endeavouring to investigate it. Although single-photon emission CT with ⁹⁹Tc-sestamibi is in theory an appropriate technique here, the radioisotope was unfortunately injected no matter what the patency of the culprit coronary artery was. In those patients with a patent coronary artery at admission, ⁹⁹Tc-sestamibi might have escaped into the ischaemic bed, and thereby the size of the area at risk might have been underestimated. Collateral flow is another major determinant of infarct size, with a collateral circulation being visible at admission coronary angiography in nearly 20% of patients with STEMI. These patients are endogenously protected and develop small infarcts even without any protective intervention; including such a subpopulation into trials that examine reductions in infarct size, as in today’s study, substantially lowers the statistical power
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False-coloured image of ischaemic heart
Comment
700 www.thelancet.com Vol 375 February 27, 2010
Balancing the benefits of statins versus a new risk—diabetesAll drugs have side-effects. Indeed, all interventions (including even exercise programmes) have side-effects. The balance in medicine is to evaluate the benefits and weigh them against the risks. For statins, the benefits in reducing clinical events have been shown in a multitude of trials with more than 500 000 patient-years of treatment.1 This benefit has led to their inclusion in national guidelines as a key component of both primary and secondary prevention.2–4 The side-effects most often discussed with statins are increases in liver-function tests, muscle aches, and, more rarely, rhabdomyolysis.
Most recently, development of diabetes was suggested in a large randomised trial of rosuvastatin for primary prevention.5 Many questions arose: was this a true finding or the play of chance; and, if real, was the finding particular to this statin or a class effect? Then, additional questions we would ask are: is the effect a large or small one? And how does this risk balance against the known benefits of statins? Has this effect been seen
with other drugs? Finally, what are the practical clinical implications—ie, what do I need to do for my patients?
In The Lancet today, Naveed Sattar and colleagues6 present a collaborative meta-analysis of randomised trials with statins in which they address many of these issues by collecting data from 13 large placebo-controlled trials. These meta-analysts found that there was a consistent finding of a higher risk of developing diabetes. Over a mean of 4 years in just over 91 000 individuals, 2226 assigned statins and 2052 assigned control treatment developed diabetes. There was a 9% increase in risk (odds ratio 1·09; 95% CI 1·02–1·17)—ie, a small increased risk. The risk seemed to be present mostly in older patients, with no risk seen in younger patients (age ≤60 years). They found little statistical heterogeneity between trials and statins. Thus this finding does seem to be a class effect of statins.
This effect seems almost paradoxical—how could a statin increase the risk of developing diabetes
of the study. Taking into account these determinants of infarct size in the experimental design of future trials will help to improve their accuracy and power to explore future treatments that aim to prevent lethal reperfusion injury.
At a time of major difficulties in supporting the cost of our health-care systems, Bøtker and colleagues have shown that a non-invasive, simple, safe, and cheap intervention, possibly done by a paramedic before hospital admission, can significantly increase myocardial salvage; they have also shown the benefit of an integrated prehospital and inhospital therapeutic strategy. Following the lessons of experimental models, Bøtker and colleagues were able to show that remote conditioning can significantly increase myocardial salvage in patients with STEMI, which suggests that the technique might represent a new powerful treatment option for such patients. Their study confirms proof-of-concept clinical studies and suggests that lethal reperfusion injury is the next major target for the treatment of patients with acute myocardial infarction. Any enthusiasm arising from this encouraging study must, however, be tempered by the need to show actual clinical benefit in larger-scale clinical studies.
*Michel Ovize, Eric BonnefoyHospices Civils de Lyon, Hôpital Cardio-vasculaire et Pneumologique and University Lyon 1, Lyon, France (MO, EB); and Hospices Civils de Lyon, Hôpital Cardio-vasculaire et Pneumologique and INSERM 886, 69008 Lyon, France (MO) [email protected]
We declare that we have no conflicts of interest.
1 Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124–36.
2 Zhao Z-Q, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003; 285: H579–88.
3 Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation 2005; 112: 2143–48.
4 Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008; 359: 473–81.
5 Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993; 87: 893–99.
6 Kharbanda RK, Nielsen TT, Redington AN. Translation of remote ischaemic preconditioning into clinical practice. Lancet 2009; 374: 1557–65.
7 Bøtker HE, Kharbanda R, Schmidt MR, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 2010; 375: 727–34.
8 Burns RJ, Gibbons RJ, Yi Q, et al. The relationships of left ventricular ejection fraction, end–systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis. J Am Coll Cardiol 2002; 39: 30–36.
9 Gibbons RJ, Valeti US, Araoz PA, Jaffe AS. The quantification of infarct size. J Am Coll Cardiol 2004; 44: 1533–42.
10 Kin H, Zhao ZQ, Sun HY, et al. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 2004; 62: 74–85.
Improved long-term clinical outcomes in patientswith ST-elevation myocardial infarctionundergoing remote ischaemic conditioning as anadjunct to primary percutaneous coronaryinterventionAstrid D. Sloth1*, Michael R. Schmidt1, Kim Munk1, Rajesh K. Kharbanda2,Andrew N. Redington3, Morten Schmidt4, Lars Pedersen4, Henrik T. Sørensen4,and Hans Erik Bøtker1, CONDI Investigators1Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark; 2Oxford University Hospitals, John Radcliffe Hospital, Oxford, UK; 3Division of Cardiology, Hospital for SickChildren, Toronto, Canada; and 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark
Received 1 July 2013; revised 27 July 2013; accepted 14 August 2013
Aims Remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction increasesmyocardial salvage. We investigated the effectof remote ischaemic conditioningon long-term clinical outcome.
Methodsand results
From February 2007 to November 2008, 333 patients with a suspected first acute ST-elevation myocardial infarctionwere randomized to receive primary percutaneous coronary intervention with (n ¼ 166) or without (n ¼ 167)remote ischaemic conditioning (intermittent arm ischaemia through four cycles of 5-min inflation followed by 5-min de-flationof ablood-pressurecuff). Patient follow-upextended fromthe randomizationdateuntil anoutcome, emigrationorJanuary 2012 (median follow-up ¼ 3.8 years). The primary endpoint was major adverse cardiac and cerebrovascularevents (MACCE)—a composite of all-cause mortality, myocardial infarction, readmission for heart failure, and ischaemicstroke/transient ischaemic attack. The individual components of the primary endpoint comprised the secondary end-points. Outcomes were obtained from Danish nationwide medical registries and validated by medical record reviewand contact to patients’ general practitioner. In the per-protocol analysis of 251 patient fulfilling trial criteria, MACCEoccurred for 17 (13.5%) patients in the intervention group compared with 32 (25.6%) patients in the control group, yield-ing a hazard ratio (HR) of 0.49 (95% confidence interval: 0.27–0.89, P ¼ 0.018). The HR for all-cause mortality was 0.32(95% confidence interval: 0.12–0.88, P ¼ 0.027). Although lower precision, the HRs were also directionally lower for allother secondary endpoints.
Conclusion Remote ischaemic conditioning before primary percutaneous coronary intervention seemed to improve long-term clini-cal outcomes in patients with ST-elevation myocardial infarction.
IntroductionAcute myocardial infarction remains a major cause of morbidity andmortality.1 While advances in reperfusion strategies have improvedclinical outcomes,2 –4 evidence is growing that reperfusion injuryoccurs after revascularization.5,6 Limiting reperfusion injury hastherefore become a treatment target. Remote ischaemic condition-ing is a new approach, in which brief episodes of ischaemia distantfrom the heart are used to protect against myocardial reperfusioninjury.7– 9 The stimulus can be applied in a simple, low cost mannerusing cycles of inflation/deflation of a blood-pressure cuff placedaround the upper arm.10– 13
We have shown that remote ischaemic conditioning initiated in theambulance during hospital transport for primary percutaneous cor-onary intervention in patients with ST-elevation myocardial infarc-tion improves myocardial salvage evaluated by single photonemission computed tomography (SPECT).14 In an echocardiographicsubtrial, we have furthermore demonstrated a modest increase inshort-term left ventricular function inpatientswith a largemyocardialarea at risk and in patients with left anterior descending artery (LAD)infarcts.15 However, no trial data exist on long-term clinical outcome
associated with remote ischaemic conditioning in patients with acutemyocardial infarction.
We therefore examined whether the short-term benefits ofremote ischaemic conditioning as an adjunct to primary percutan-eous coronary intervention translated into improved long-term clin-ical outcomes in patients with ST-elevation myocardial infarction.
Methods
Design, trial setting, and participantsThe parent trial was a randomized, controlled trial performed in the De-partment of Cardiology, Aarhus University Hospital, Denmark. Patientinclusion and randomization have been described in detail elsewhere.14
The present trial included all randomized patients from the parent trial.In brief, patients were enrolled in the parent trial from February 2007to November 2008. Criteria for inclusion were as follows: (i) age ≥18years, (ii) symptom duration of ≤12 h prior to admission, and (iii)ST-segment elevation ≥0.1 mV in two or more contiguous electrocar-diogram leads. Patients were excluded from the analysis based on thefollowing criteria: (i) diagnosis not confirmed upon hospital arrival,(ii) history of previous myocardial infarction, (iii) previous coronary
Figure 1 Trial flowchart. RIC, remote ischaemic conditioning; pPCI, primary percutaneous coronary intervention; LV, left ventricular; SPECT,single photon emission computed tomography; MACCE, major adverse cardiac and cerebrovascular events.
Table 1 Number of patients (%) and hazard ratios (95% CI) for the primary composite endpoint of any major adverse cardiac and cerebrovascular events (MACCE)and for the secondary endpoints (all-cause mortality, myocardial infarction, readmission for heart failure, and ischaemic stroke/transient ischaemic attack) in thefollow-up period
artery bypass grafting (CABG), and (iv) chest pain .12 h prior to admis-sion.
In total, 333 patients with a tentative diagnosis of ST-elevation myocar-dial infarction were enrolled during ambulance transfer and randomizedto receive remote ischaemic conditioning as an adjunct to primary percu-taneous coronary intervention (n ¼ 166) or to receive standard treat-ment with primary percutaneous coronary intervention alone (n ¼167). The remote ischaemic conditioning intervention was initiated inthe ambulance during transport to the interventional centre using inter-mittent arm ischaemia. Arm ischaemia was achieved by means of fourcycles of alternating 5-min inflation (200 mmHg) followed by 5-min defla-tion of a blood pressure cuff placed on the upper arm. Of the 333 patientsinitially enrolled in the pre-hospital setting, 82 patients were excluded onhospital arrival because they did not meet the trial criteria, as describedabove (Figure 1).
EndpointsThe primary endpoint was major adverse cardiac and cerebrovascularevents (MACCE), defined as a composite of all-cause mortality, myocar-dial infarction, readmission for heart failure, and ischaemic stroke/transient ischaemic attack. The individual components of the primaryendpoint comprised the secondary endpoints.
All-cause mortality was defined as death from any cause in the follow-up period. Death causes were divided into cardiac and non-cardiac deathcauses. Cardiac death causes were defined as death from an evidentcardiac cause or death from unknown cause.
Myocardial infarction was defined as a myocardial reinfarction (within28 days of index admission) or a recurrent myocardial infarction occur-ring .28 days after index admission. The diagnoses of myocardial infarc-tion were made according to existing guidelines,16 and furthermoredivided into ST-elevation myocardial infarction and non-ST-elevationmyocardial infarction.
Readmission for heart failure was defined as readmission for decom-pensated chronic heart failure, acute heart failure (lung oedema or car-diogenic shock), or device implantation due to chronic heart failure[biventricular pacemaker and/or prophylactic implantable cardioverterdefibrillator (ICD)] in the follow-up period.
Ischaemic stroke was defined as new neurological deficit persistingfor .24 h and a computed tomography (CT) or magnetic resonanceimaging (MRI) verifying acute brain infarction and transient ischaemicattack as new neurological deficit resolving within 24 h and a CT scanor MRI without acute brain infarction in the follow-up period.
Data collectionWe followed all trial patients from the date of randomization untilan outcome, emigration, or January 2012, whichever occurred first.Outcome data were collected from Danish nationwide medical regis-tries. Each Danish citizen is given a unique 10-digit personal identificationnumber at birth or upon immigration, which can be used to link dataamong administrative and medical registries.17
We identified all-cause mortality from the Danish Civil RegistrationSystem.17 This registry has collected information on the vital status ofall Danish citizens, including date of death, since 1968. All death certifi-cates contain theunderlying andcontributing causesof deathandare sub-mitted to the Danish Registry of Causes of Death by the physician whoverified the death. We used the Danish Registry of Causes of Death toidentify cardiac and non-cardiac deaths.18
We identified all non-fatal outcomes from the Danish National Regis-try of Patients.19 This registry has collected data on all hospital admissionssince 1977. At discharge, each hospitalization is coded by the treating
physician with one primary diagnosis, and, when appropriate, one ormore secondary diagnoses, according to the International Classificationof Diseases (ICD) system, 10th revision (from 1994 onwards).
To ensure high-quality data, we validated all cardiovascular readmis-sions and causes of death using medical records or by contacting thepatient’s general practitioner. Events occurring during the patients’index admission were also obtained from medical records. Trial staffmembers responsible for collection and analyses of follow-up datawere blinded to treatment assignment.
The trial protocolwasapprovedby theRegionalEthicsCommittee andthe Danish Data Protection Agency. The trial was registered with Clini-calTrials.gov, number NCT01665365.
Statistical analysesTwo types of analyses were performed: (i) a per-protocol analysis ofpatients fulfilling trial criteria (n ¼ 251) and (ii) an intention-to-treat ana-lysis of all randomized patients (n ¼ 333). We used Cox proportionalhazards regression to calculate hazard ratios (HRs) with 95% confidenceintervals (CIs), with and without adjustment for differences in baselinecharacteristics (age, sex, and hypertension). Using the Kaplan–Meierestimator, we illustrated graphically the cumulative incidence functionof MACCE, all-cause mortality, cardiac mortality, and non-cardiacmortality.
A two-tailed P-value ,0.05 was considered statistically significant.Statistical analyses were conducted using the SAS software (version 9.2).
ResultsFollow-up data were available for all 333 randomized patients, withno patients lost to follow-up. There was no difference in follow-uptime between the intervention and control groups [median follow-up time ¼ 3.8 years (95% CI: 3.3 years to 4.2 years) and maximumfollow-up time ¼ 4.9 years]. Baseline characteristics and medicalprocedure data have previously been published in detail and didnot differ in the two groups except for hypertension, which wasmore common in the intervention group.14 Adjustments for thedifferences in baseline characteristics did not change the resultssubstantially, and we therefore only report the crude HRs.
In the per-protocol analysis (n ¼ 251), the primary compositeendpoint (MACCE) occurred in 17 (13.5%) patients in the inter-vention group and in 32 (25.6%) patients in the control group(Table 1). The HR for MACCE was 0.49 (95% CI: 0.27–0.89, P ¼0.018) in favour of the intervention (Figure 2). When the MACCEdefinition included only cardiac mortality, rather than all-causemortality, the composite endpoint was experienced in 15(11.9%) patients in the intervention group and in 25 (20.0%)patients in the control group, yielding an HR of 0.56 (95% CI:0.30–1.06, P ¼ 0.075).
Among the secondary endpoints, all-cause mortality wasreduced in the intervention group compared with the controlgroup [5 deaths (4.0%) vs. 15 deaths (12.0%), HR ¼ 0.32 (95% CI:0.12–0.88, P ¼ 0.027)]. Causes of death are listed in Table 2,where cancer was the most common non-cardiac death cause.The HRs for MACCE were reduced independently of vesselpatency before procedure and infarct location (Table 1). Althoughlower precision, the HRs were also directionally lower for allother secondary endpoints (myocardial infarction, readmission for
A.D. Sloth et al.Page 4 of 8
heart failure, and ischaemic stroke/transient ischaemic attack). Thecumulative incidence curves for MACCE, all-cause mortality,cardiac mortality and non-cardiac mortality are shown in
Figure 3A–D. The intention-to-treat analysis supported the per-protocol analysis (Table 1 and Supplementary material online,Figures S4 and S5A–D).
Table 2 Death causes (per-protocol and intention-to-treat analysis)
RIC 1 pPCI (n ¼ 166) pPCI (n ¼ 167)
Cardiac death (n ¼ 4) Cardiac death (n ¼ 9)
(1) Cardiac tamponade (perforated LAD)a
(2) Respiratory insufficiency (combinationof pulmonaryoedema/acuteexacerbation in chronic obstructive pulmonary disease)
(3) Cardiogenic shocka
(4) Cardiac arrest (found dead at home – autopsy not performed)
(1) Sudden cardiac arresta
(2) Cardiogenic shocka
(3) Sudden cardiac arresta
(4) Repeated stent thrombosis(5) Sudden cardiac arrest (during readmission for myocardial infarct/heart failure)(6) Cardiac arrest (found dead at home—autopsy not performed)(7) Chronic heart failure(8) Cardiogenic shocka
(9) Pulmonary oedemaa
Non-cardiac death (n ¼ 7) Non-cardiac death (n ¼ 12)
(1) Cancer (diffuse large B-cell lymphoma)a
(2) Post-operative bleeding (surgery for rectal tumour)a
(3) Cancer (bladder cancer)(4) Parkinson’s disease(5) Cancer (breast cancer)a
(6) Cancer (acute myeloid leukaemia)(7) Diffuse bleeding/thrombocytopenia (aetiology unknown)
(1) Post-operative respiratory insufficiency and bleeding (surgery for rectalcancer)a
(2) Cancer (lung cancer)a
(3) Cancer (colon cancer)a
(4) Sepsis (peritonitis)a
(5) Cancer (prostate cancer)a
(6) Suspected cancer (the patient was not interested in further diagnosticexamination)a
(7) Alcohol intoxication(8) Cancer (oesophagus cancer)(9) Cancer (cerebral cancer)a
Figure 2 Hazard ratio for the primary composite endpoint (major adverse cardiac and cerebrovascular events) and for the secondary endpoints(all-cause mortality, myocardial infarction, readmission for heart failure, and ischaemic stroke/transient ischaemic attack) in the follow-up period(per-protocol analysis).
Improved long-term clinical outcomes after remote conditioning in STEMI Page 5 of 8
DiscussionWe found that remote ischaemic conditioning as an adjunct toprimary percutaneous coronary intervention in patients withST-elevation myocardial infarction seemed to improve long-termclinical outcomes.
This is the first trial to evaluate the effect of remote ischaemicconditioning as an adjunct to primary percutaneous coronary inter-vention on long-term clinical outcomes in patients with myocardialinfarction. A recent meta-analysis including 23 randomized trialsinvestigating the effect of remote ischaemic conditioning on clinicaloutcomes showed a reduction in cardiac biomarker release and peri-procedural myocardial infarction, but did not demonstrate an effecton major adverse cardiovascular events or mortality.20 However, themeta-analysis was mainly based on trials in low-risk patients undergo-ing elective cardiac procedures and only investigated short-term
clinical outcomes, i.e. up to 6 months after the index event. Onlyone trial besides our parent trial was conducted in high-risk patientswith ST-elevation myocardial infarction and this trial did not evaluateclinical outcomes, but only the effect of remote ischaemic condition-ing on the release of biochemical myocardial necrosis markers andST-segment resolution.21
More recently, results from the CRISP stent trial in patientsundergoing elective percutaneous coronary intervention havedemonstrated a lower MACCE rate in the remote ischaemic precon-ditioning group compared with the control group after 6 years offollow-up [23 vs. 36, HR ¼ 0.58 (95% CI: 0.35–0.97), P ¼ 0.039].22
Additionally, a trial in patients undergoing elective CABG rando-mized to remote ischaemic preconditioning or standard therapyhas showed a reduction in MACCE [13.9 vs. 18.9%, HR ¼ 0.32(95% CI: 0.14–0.71), P ¼ 0.05] and all-cause mortality [1.9 vs.6.9%, HR ¼ 0.27 (95% CI: 0.08–0.98), P ¼ 0.046] after a mean
Figure3 (A) Cumulative incidence (%) of major adverse cardiac and cerebrovascularevents (MACCE) by year since randomization (per-protocolanalysis). P ¼ 0.010. (B) Cumulative incidence (%) of all-cause mortality by year since randomization (per-protocol analysis). P ¼ 0.019. (C) Cumu-lative incidence of cardiac mortality (%) by year since randomization (per-protocol analysis). P ¼ 0.248. (D) Cumulative incidence of non-cardiacmortality (%) by year since randomization (per-protocol analysis). P ¼ 0.045.
A.D. Sloth et al.Page 6 of 8
follow-updurationof1.54years.23 While these two trials reportedaneffect of remote ischaemic conditioning on long-term clinical out-comes in a priori low-risk patients undergoing elective cardiac proce-dures, our results demonstrate an effect of remote ischaemicconditioning on long-term clinical outcomes in patients undergoingprimary percutaneous coronary intervention for ST-elevation myo-cardial infarction.
We have presented per-protocol as well as intention-to-treatdata. Although intention-to-treat data increase sample size andhence statistical power, we focused on the per-protocol analysis inaccordance with the conclusion in our parent trial that was basedon an improvement in myocardial salvage index per-protocol.14
The reduction in our primary endpoint MACCE was mainly drivenby a reduction in all-cause mortality. Evaluating specific death causes,the point estimates suggested a reduction in both cardiac and non-cardiac mortality. The reduction in cardiac mortality was expectedfrom the parent trial results. The reduction in non-cardiac mortalitywas not and most likely arose by chance. Importantly, the results forMACCE when excluding non-cardiac mortality supported our con-clusion. We note that the previously demonstrated improvementin myocardial salvage index and left ventricular function may translateinto a reduction in the post-infarction heart failure rate driven byfewer device implantations due to chronic heart failure. However,the overall number of post-infarction heart failure diagnoses wastoo low to draw firm conclusions.
In the parent trial a subgroup analysis of myocardial salvage indexstratified by vessel patency and infarct location showed that the effectof remote ischaemic conditioning was most pronounced in patientswith an occluded vessel on admission and in patients with LADinfarcts.14 Although our subgroup analyses did not allow firm conclu-sions, our results do not reject the assumption that a beneficial effectis predominantly achieved in patients with an occluded vessel on ad-mission consistent with the hypothesis that the effect of remote is-chaemic conditioning is mainly associated with an attenuation ofreperfusion injury. On the other hand, the clinical effect of remote is-chaemic conditioning was independent on infarct location, indicatingthat all patients with ST-elevation myocardial infarction may benefitfrom this low-risk treatment.
The present trial has limitations. The power calculation in theparent trial was based on the myocardial salvage index. Here, wereport long-term clinical outcomes. Importantly, despite wide CIsdue to the sample size, all point estimates supported a beneficialeffect. We defined heart failure as readmission for heart failure.We may have underestimated the rate of heart failure, because out-patient diagnoses were not included. However, this potential mis-classification would bias the estimates towards null and thus cannotexplain the reduced HR for heart failure. Substantial confounding isless likely owing to the randomized design and because theintention-to-treat analysis supported the results from the per-protocol analysis. Also, adjustment for the difference in hypertensionfrequency among the groups at baseline did not change the results.
The outcome of this first trial to evaluate the effect of remote is-chaemic conditioning on long-term clinical outcomes in patientswith ST-elevation myocardial infarction is encouraging. A simple,cost-effective intervention, which can easily be applied in the pre-hospital setting in patients with acute cardiac events, may in facthave the potential to reduce morbidity and mortality. However,
our results need to be confirmed in a larger multicentre trialbefore remote ischaemic conditioning can be implemented in guide-lines as an adjunct to primary percutaneous coronary intervention.
Supplementary materialSupplementary material is available at European Heart Journal online.
Authors’ contributionsA.D.S. had full access to all data in the trial and takes responsibility forthe integrity of the data and accuracy of the data analysis.
FundingThis work was supported by the Danish Council for Strategic Research(11-115818) and Foundation Leducq (06CVD). The trial was designed,conducted, analysed, interpreted, and reported independently of bothfunding sources.
Conflict of interest: All authors have completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest. M.R.S.,R.K.K., A.N.R., and H.E.B. are shareholders in CellAegis. No otherdisclosures were reported.
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