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Figure 1.
CONSORT Study Flow Diagram
CONSORT Study Flow Diagram

Randomization of patients in the Third Danish Study of Optimal Acute Treatment of Patients With ST Elevation Myocardial Infarction–Ischemic Postconditioning (DANAMI-3–iPOST). CABG indicates coronary artery bypass grafting; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; and TIMI, thrombolysis in myocardial infarction.

aTwenty patients had 2 exclusion criteria.

bGrades range from 0 to 3, with 3 indicating higher flow.

Figure 2.
Kaplan-Meier Curves of the Primary End Point
Kaplan-Meier Curves of the Primary End Point

A, Event rates of the combined primary outcome (all-cause mortality [B] and hospitalization for heart failure [C]) in the Third Danish Study of Optimal Acute Treatment of Patients With ST Elevation Myocardial Infarction–Ischemic Postconditioning (DANAMI-3–iPOST) are shown from the time of the primary percutaneous intervention to 40 months after the index treatment. The Cox proportional hazards model was used to calculate hazard ratios (HRs), 95% CIs, and P values.

Table 1.  
Characteristics of the Patients at Baseline
Characteristics of the Patients at Baseline
Table 2.  
Procedural Data and Medication Given at Dischargea
Procedural Data and Medication Given at Dischargea
Table 3.  
Clinical Outcome According to Treatment Allocation
Clinical Outcome According to Treatment Allocation
1.
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Hahn  JY, Song  YB, Kim  EK,  et al.  Ischemic postconditioning during primary percutaneous coronary intervention: the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction (POST) randomized trial.  Circulation. 2013;128(17):1889-1896.PubMedGoogle ScholarCrossref
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Eitel  I, Stiermaier  T, Rommel  KP,  et al.  Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial.  Eur Heart J. 2015;36(44):3049-3057.PubMedGoogle ScholarCrossref
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Høfsten  DE, Kelbæk  H, Helqvist  S,  et al; DANAMI 3 Investigators.  The Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: ischemic postconditioning or deferred stent implantation versus conventional primary angioplasty and complete revascularization versus treatment of culprit lesion only: rationale and design of the DANAMI 3 trial program.  Am Heart J. 2015;169(5):613-621.PubMedGoogle ScholarCrossref
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Kelbæk  H, Høfsten  DE, Køber  L,  et al.  Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): an open-label, randomised controlled trial.  Lancet. 2016;387(10034):2199-2206.PubMedGoogle ScholarCrossref
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Engstrøm  T, Kelbæk  H, Helqvist  S,  et al; DANAMI-3—PRIMULTI Investigators.  Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3–PRIMULTI): an open-label, randomised controlled trial.  Lancet. 2015;386(9994):665-671.PubMedGoogle ScholarCrossref
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World Medical Association. WMA Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. 2017. http://www.wma.net/en/30publications/10policies/b3/. Accessed February 8, 2017.
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European Medicines Agency. European Guideline for Good Clinical Practice E6(R2). 2015. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/08/WC500191488.pdf. Accessed February 8, 2017.
21.
Lønborg  J, Vejlstrup  N, Kelbæk  H,  et al.  Final infarct size measured by cardiovascular magnetic resonance in patients with ST elevation myocardial infarction predicts long-term clinical outcome: an observational study.  Eur Heart J Cardiovasc Imaging. 2013;14(4):387-395.PubMedGoogle ScholarCrossref
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Eitel  I, de Waha  S, Wöhrle  J,  et al.  Comprehensive prognosis assessment by CMR imaging after ST-segment elevation myocardial infarction.  J Am Coll Cardiol. 2014;64(12):1217-1226.PubMedGoogle ScholarCrossref
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Schröder  R.  Prognostic impact of early ST-segment resolution in acute ST-elevation myocardial infarction.  Circulation. 2004;110(21):e506-e510.PubMedGoogle ScholarCrossref
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Cohen  MV, Yang  XM, White  J, Yellon  DM, Bell  RM, Downey  JM.  Cangrelor-mediated cardioprotection requires platelets and sphingosine phosphorylation.  Cardiovasc Drugs Ther. 2016;30(2):229-232.PubMedGoogle ScholarCrossref
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Tsang  A, Hausenloy  DJ, Mocanu  MM, Yellon  DM.  Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway.  Circ Res. 2004;95(3):230-232.PubMedGoogle ScholarCrossref
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Manintveld  OC, Te Lintel Hekkert  M, van den Bos  EJ,  et al.  Cardiac effects of postconditioning depend critically on the duration of index ischemia.  Am J Physiol Heart Circ Physiol. 2007;292(3):H1551-H1560.PubMedGoogle ScholarCrossref
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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(9716):727-734.PubMedGoogle ScholarCrossref
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Lønborg  J, Vejlstrup  N, Kelbæk  H,  et al.  Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction.  Eur Heart J. 2012;33(12):1491-1499.PubMedGoogle ScholarCrossref
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Hausenloy  DJ, Kharbanda  R, Rahbek Schmidt  M,  et al.  Effect of remote ischaemic conditioning on clinical outcomes in patients presenting with an ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.  Eur Heart J. 2015;36(29):1846-1848.PubMedGoogle Scholar
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    Citation

    Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Clemmensen P, Holmvang L, Jørgensen E, Pedersen F, Saunamaki K, Ravkilde J, Tilsted H, Villadsen A, Aarøe J, Jensen SE, Raungaard B, Bøtker HE, Terkelsen CJ, Maeng M, Kaltoft A, Krusell LR, Jensen LO, Veien KT, Kofoed KF, Torp-Pedersen C, Kyhl K, Nepper-Christensen L, Treiman M, Vejlstrup N, Ahtarovski K, Lønborg J, Køber L, for the Third Danish Study of Optimal Acute Treatment of Patients With ST Elevation Myocardial Infarction–Ischemic Postconditioning (DANAMI-3–iPOST) Investigators. Effect of Ischemic Postconditioning During Primary Percutaneous Coronary Intervention for Patients With ST-Segment Elevation Myocardial InfarctionA Randomized Clinical Trial. JAMA Cardiol. 2017;2(5):490–497. doi:10.1001/jamacardio.2017.0022

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Original Investigation
May 2017

Effect of Ischemic Postconditioning During Primary Percutaneous Coronary Intervention for Patients With ST-Segment Elevation Myocardial InfarctionA Randomized Clinical Trial

Author Affiliations
  • 1Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • 2Department of Cardiology, Roskilde Hospital, Roskilde, Denmark
  • 3Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
  • 4Department of Cardiology, Skejby University Hospital, Skejby, Denmark
  • 5Department of Cardiology, Odense University Hospital, Odense, Denmark
  • 6Department of Clinical Epidemiology, Aalborg University Hospital, Aalborg, Denmark
  • 7Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
JAMA Cardiol. 2017;2(5):490-497. doi:10.1001/jamacardio.2017.0022
Key Points

Question  Does ischemic postconditioning of the heart during primary percutaneous coronary intervention improve clinical outcome?

Finding  In a Danish multicenter, randomized clinical trial of 1234 patients with onset of symptoms within 12 hours, ST-segment elevation myocardial infarction, and thrombolysis in myocardial infarction grade 0-1 flow in the infarct-related artery at arrival, all-cause hopitalization or death occurred in 11.2% of 617 patients who underwent percutaneous coronary intervention (including stent implantation) and 10.5% of 617 patients who underwent postconditioning (4 repeated balloon occlusions of 30 seconds followed by 30 seconds of reperfusion immediately after opening of the infarct-related artery and before stent implantation).

Meaning  Ischemic postconditioning does not improve clinical outcome in patients with ST-segment elevation myocardial infarction.

Abstract

Importance  Ischemic postconditioning of the heart during primary percutaneous coronary intervention (PCI) induced by repetitive interruptions of blood flow to the ischemic myocardial region immediately after reopening of the infarct-related artery may limit myocardial damage.

Objective  To determine whether ischemic postconditioning can improve the clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI).

Design, Setting, And Participants  In this multicenter, randomized clinical trial, patients with onset of symptoms within 12 hours, STEMI, and thrombolysis in myocardial infarction (TIMI) grade 0-1 flow in the infarct-related artery at arrival were randomized to conventional PCI or postconditioning. Inclusion began on March 21, 2011, through February 2, 2014, and follow-up was completed on February 2, 2016. Analysis was based on intention to treat.

Interventions  Patients were randomly allocated 1:1 to conventional primary PCI, including stent implantation, or postconditioning performed as 4 repeated 30-second balloon occlusions followed by 30 seconds of reperfusion immediately after opening of the infarct-related artery and before stent implantation.

Main Outcome and Measures  A combination of all-cause death and hospitalization for heart failure.

Results  During the inclusion period, 1234 patients (975 men [79.0%] and 259 women [21.0%]; mean [SD] age, 62 [11] years) underwent randomization in the trial. Median follow-up was 38 months (interquartile range, 24-58 months). The primary outcome occurred in 69 patients (11.2%) who underwent conventional primary PCI and in 65 (10.5%) who underwent postconditioning (hazard ratio, 0.93; 95% CI, 0.66-1.30; P = .66). The hazard ratios were 0.75 (95% CI, 0.49-1.14; P = .18) for all-cause death and 0.99 (95% CI, 0.60-1.64; P = .96) for heart failure.

Conclusions and Relevance  Routine ischemic postconditioning during primary PCI failed to reduce the composite outcome of death from any cause and hospitalization for heart failure in patients with STEMI and TIMI grade 0-1 flow at arrival.

Trial Registration  clinicaltrials.gov Identifier: NCT01435408

Introduction

In patients with ST-segment elevation myocardial infarction (STEMI), the recommended therapy is primary percutaneous coronary intervention (PCI).1 Although acute restoration of myocardial blood flow is overall beneficial, the procedure in itself may jeopardize the myocardium. This phenomenon, known as reperfusion injury, may account for as much as 50% of the final myocardial infarct size, a major determinant of the prognosis in patients with STEMI.2,3

Experimental and clinical proof-of-concept studies4,5 have demonstrated that reopening of the infarcted artery followed by repetitive brief interruptions of blood flow before establishment of final reperfusion may protect the myocardium against reperfusion injury. This technique, known as mechanical or ischemic postconditioning, is safe, easy to perform, and without additional cost. In a pig model of ischemia reperfusion, postconditioning resulted in an increase in myocardial salvage by 52%,5 which is in accordance with findings in dog (31%-44% increased salvage), mouse (25% increased salvage), and rabbit (68% increased salvage) models.6,7 In contrast to those marked effects in animal models, studies of the effect of postconditioning on surrogate markers in humans have shown conflicting results.8 Lønborg et al4 found an increase in myocardial salvage ratio evaluated by magnetic resonance imaging; correspondingly, Staat et al,9 Thibault et al,10 and Xue et al11 noted a decrease in enzyme leakage.6,7 On the other hand, Sörensson et al,12 Freixa et al,13 and Hahn et al14 did not find an effect of postconditioning in humans with STEMI.6,7 A recent intermediate-sized trial found a significant increase in myocardial salvage when postconditioning was combined with remote ischemic conditioning but no effect of postconditioning alone.15 Thus, whether improvements in these surrogate markers translate into improved clinical outcomes with regard to hard end points for patients undergoing primary PCI has to be investigated in an adequately sized randomized trial. Therefore, we tested the effect of postconditioning in addition to primary PCI on survival and hospitalization for heart failure in patients with STEMI and thrombolysis in myocardial infarction (TIMI) grade 0-1 flow (grades range from 0 to 3, with higher grades indicating higher flow).

Methods
Population

The Third Danish Study of Optimal Acute Treatment of Patients With ST Elevation Myocardial Infarction–Ischemic Postconditioning (DANAMI-3–iPOST) is a part of the DANAMI-3 program conducted at all 4 large, primary PCI centers in Denmark. The program encompassed 3 trials evaluating the effect of ischemic postconditioning (DANAMI-3–iPOST), deferred stenting (DANAMI-3–DEFER),16,17 and complete revascularization (DANAMI-3–PRIMULTI).16,18 The study protocol has been described in detail16 and is available in Supplement 1. The academic steering committee of the trial designed the protocol, which complied with the Helsinki Declaration19 and the European guideline for good clinical practice.20 The protocol and any amendments, including written information and consent forms, were formally approved by the local ethics committee (according to local regulations at the Heart Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Skejby University Hospital, University of Aarhus, Aarhus, Denmark; Aalborg University Hospital, University of Aalborg, Aalborg, Denmark; and Odense University Hospital, University of Southern Denmark, Odense, Denmark) before initiation of the trial. All randomized patients provided written informed consent. All data were stored at the Clinical Trial Unit of Rigshospitalet, Cohenhagen, Denmark.

Patients were randomized to primary PCI performed with postconditioning vs conventional primary PCI (Figure 1). Patients could be included in the trial within 12 hours of onset of symptoms with an electrocardiogram demonstrating greater than 0.1 mV ST-segment elevation and an initial angiogram demonstrating TIMI grade 0-1 flow. Major exclusion criteria included intolerance to contrast media, anticoagulants, or antithrombotic medication; unconsciousness or cardiogenic shock; stent thrombosis; indication for acute coronary artery bypass surgery; or increased risk for bleeding. Randomization was performed by the time of angiography before obtaining flow grade. Randomization was performed using the permuted-block method, with block sizes varying from 2 to 6 patients (in cases of 1:1 randomization) or 3 to 9 patients (in cases of 1:1:1 randomization) and stratified by center. The invasive PCI team, who had no further involvement in the subsequent treatment or evaluation of the patients, performed the enrollment and randomization sequences.

PCI and Study Treatment

Postconditioning was performed before stent implantation and within 60 seconds after reopening of the infarct-related artery. This timing was chosen so as to await reperfusion (TIMI grade 2-3 flow) but also to avoid missing the effect of the treatment (postconditioning within 60 seconds). TIMI grade 2-3 flow in the artery was secured by wire insertion alone, thrombectomy, or dilatation with an undersized balloon. Thereafter, a semicompliant balloon with sufficient diameter to obstruct blood flow to the peripheral vascular bed was inflated at low pressure (4-8 atm) and subsequently deflated after 30 seconds. The deflated balloon was left in situ for another 30 seconds before reinflation. Ischemic postconditioning was repeated for 4 cycles (30-second obstruction followed by 30-second reperfusion each) and followed by stent implantation.4 Cardiologists were, as part of the study instruction, only allowed to interrupt the cycles if severe adverse effects occurred (eg, ventricular fibrillation, perforation, or hemodynamic deterioration), and they were encouraged to check full occlusion of the vessel during postconditioning by small injections of contrast. The use of a second-generation drug-eluting stent was recommended, and the choice of additional use of bivalirudin and/or glycoprotein IIb/IIIa antagonist was left to the discretion of the operator. All patients received intracoronary nitroglycerine as standard therapy. Intracoronary adenosine was allowed at the discretion of the operator. β-Blocker therapy was not recommended before PCI but encouraged as oral administration after. Standard initial dosing consisted of metoprolol succinate, 25 mg twice daily. All additional patient treatment was in accordance with contemporary guidelines.

Clinical Outcomes

An independent event committee adjudicated the protocol-specified clinical outcomes. The original primary outcome was a composite of cardiac death, reinfarction, and heart failure. After enrollment of all patients by February 2, 2014, the event committee in several cases reported that clear separation of cardiac death from cardiovascular death was difficult. Based on this information, the steering committee reconsidered the composition of the primary outcome. The assumed attenuation of myocardial damage, and thus preservation of left ventricular function after postconditioning, suggested heart failure as a pivotal component. Therefore, in August 2014, the steering committee decided to change the primary outcome to all-cause mortality and heart failure. This adjustment was made before closing the database and before any knowledge or analysis of the data. Key secondary outcomes should reflect damage of the left ventricle and were chosen thereafter, including individual components of the primary outcome, cardiovascular death, resolution of ST-segment elevation, left ventricular ejection fraction measured by echocardiography, and magnetic resonance imaging (MRI) variables.

Death was considered cardiovascular unless clearly from another cause, as determined by the event committee. Hospitalization for heart failure was defined as prolongation of the index hospitalization because of worsening of existing heart failure, development of heart failure after the primary PCI, or new presentation to an acute care facility after hospital discharge that required at least 6 hours of hospitalization with an exacerbation of heart failure requiring treatment.

At 1 PCI center, the patients underwent 2 cardiac MRI examinations. The first was performed during initial admission, and the second was performed 90 days later as previously described.21,22 The myocardial salvage index was calculated as [area at risk (mass) – infarct size (mass)]/area at risk (mass).22 The ST-segment elevation was measured in the single lead with the highest ST-segment elevation before PCI. We calculated resolution of ST-segment elevation as the difference between maximum ST-segment elevation before PCI and 60 minutes after reperfusion as previously described.23 The study data and safety monitoring board chair and site-specific independent study monitors reviewed all adverse event reports to ensure safe study implementation.

Statistical Analysis

For the DANAMI-3–iPOST study, we estimated that the annual rate of the primary outcome would be 11% in the control group. With an inclusion period of 2.5 years and a minimum follow-up of 2 years, we would be able to detect a relative reduction in the primary end point of 25% with a 2-sided α level of .05 and a power of 80% by enrolling 1100 patients. The primary analysis was conducted in the intention-to-treat population. Differences between groups in time-to-event end points were assessed with the log-rank test. Survival probabilities are displayed using Kaplan-Meier estimates. Hazard ratios between groups were calculated using a Cox proportional hazards model with treatment group as the only covariate. Differences between group means and medians were assessed with the 2-tailed t test or Mann-Whitney test for unpaired samples. The χ2 analysis or Fisher exact test was used to test differences between proportions. The assumptions for the Cox proportional hazards models were tested and found valid. Patients lost to follow-up owing to emigration were censored at the time of emigration. Patients in the DANAMI-3 trial could be randomized second to complete vs culprit-only revascularization, and we therefore tested for the interaction between postconditioning and this second treatment. A 2-tailed P < .05 was considered to be statistically significant.

Results

From March 21, 2011, through February 2, 2014, we enrolled 1234 patients (975 men [79.0%] and 259 women [21.0%]; mean [SD] age, 62 [11] years) in the DANAMI-3–iPOST Trial (Figure 1). A total of 617 patients (489 men [79.3%]) were randomized to ischemic postconditioning and 617 patients (486 men [78.8%]) were randomized to conventional primary PCI. The median follow-up time was 38 months (range, 24-58 months). Five patients emigrated 12 to 36 months after inclusion. Except for thrombectomy, which was more frequently performed in the conventional group (423 [68.6%] vs 291 [47.2%]), baseline demographic data of the 2 patient groups were well balanced (Table 1), as were procedural characteristics and medication given at discharge (Table 2). Six patients in the postconditioning group (4 with complex multivessel disease in addition to the culprit lesion, 1 with a ventricular septal defect, and 1 with a large culprit-vessel aneurism) and 3 patients in the conventional PCI group (2 with complex multivessel disease in addition to the culprit lesion and 1 with mitral valve prolapse) were considered to be unsuitable for PCI treatment and had coronary bypass surgery performed (after heart team decision). Another 19 patients (3.1%) did not undergo postconditioning mainly owing to technical failure or unfeasible PCI. No serious adverse effects of postconditioning were seen. Ventricular tachycardia/ventricular fibrillation occurred in 12 patients (1.9%) each in the postconditioning and control groups (P = .99). All arythmias (including artrioventricular block and asystoli) occurred in 14 patients (2.3%) in the postconditioning group and 16 (2.6%) in the control group (P = .70).

The primary outcome occurred in 65 patients (10.5%) who underwent postconditioning and in 69 (11.2%) who were treated with conventional PCI alone (P = .66) (Table 3 and Figure 2). The hazard ratio (HR) for the composite outcome was 0.93 (95% CI, 0.66-1.30; P = .66). The HRs for the individual components of the composite outcome were 0.75 (95% CI, 0.49-1.14; P = .18) for all-cause death and 0.99 (95% CI, 0.60-1.64; P = .96) for heart failure hospitalization. We observed no statistically significant difference in the occurrence of cardiovascular death (HR, 0.86; 95% CI, 0.51-1.45; P = .56), recurrent myocardial infarction (HR, 1.13; 95% CI, 0.68-1.86; P = .64), or unplanned target vessel revascularization (HR, 1.35; 95% CI, 0.67-2.68; P = .40) (Table 3) between groups.

Subgroup analysis did not reveal any significant interaction between treatment modality and prespecified subgroups with diabetes, anterior infarct location, multivessel disease, or short duration of ischemia (eTable 1 in Supplement 2), and no statistically significant interaction was found between complete revascularization and postconditioning on the primary composite end point (P = .41). One hundred forty-eight patients underwent full revascularization (75 [12.2%] in the postconditioning group vs 73 [11.8%] in the control group; P = .93). Direct stenting was used more frequently in patients randomized to postconditioning (62 [10.0%] vs 32 [5.2%]; P = .001). However, adjusting for the use of direct stenting had no significant effect on the primary end point (HR, 0.97; 95% CI, 0.82-1.15; P = .70).

A total of 358 patients had acute infarct size assessed by MRI at a median of 1 day (interquartile range [IQR], 1-1 day) after the primary PCI, and 327 of these had final infarct size assessed after a median of 92 days (IQR, 88-96 days). Ischemic postconditioning did not reduce infarct size, myocardial salvage index, extent of microvascular obstruction, or left ventricular ejection fraction at 3 months (eTable 2 in Supplement 2). Resolution of ST-segment elevation measured in 475 patients was similar in the 2 treatment groups, with a median of 66% (IQR, 44%-85%) in the conventional group vs 69% (IQR, 47%-82%) in the postconditioning group (P = .68). Several criteria may affect the success of cardioprotection, the most relevant being the time of ischemia, culprit lesion location, and the size of the area at risk. However, no effect of postconditioning on final infarct size was seen in any of these subgroups (eTable 3 in Supplement 2).

Left ventricular ejection fraction by echocardiography after 18 months was higher in the postconditioning group (52.7% vs 50.8%; P = .05), with a greater difference between assignment groups when examining anterior infarcts separately (49.5% vs 45.9%; P = .04). Periprocedural myocardial infarction (5 [0.8%] in both groups; P > .99), bleeding requiring transfusion or surgery (42 [6.8%] vs 49 [7.9%], respectively; P = .45), contrast-induced nephropathy (peak creatinine level, 0.87 [IQR, 0.75-1.01] vs 0.86 [IQR, 0.72-1.02] mg/dL, respectively; P = .81) (to convert to micromoles per liter, multiply by 88.4), or stroke (7 [1.1%] vs 8 [1.3%], respectively; P > .99) occurred in few patients, with no statistically significant differences between the 2 groups.

Discussion

In patients with STEMI and TIMI grade 0-1 flow in the infarct-related artery at arrival, 4 cycles of ischemic postconditioning within 60 seconds after reopening of the culprit vessel did not result in a reduction of the primary composite outcome of all-cause death and hospitalization for heart failure. Postconditioning, first examined in a dog model by Zhao et al,6 is applied subsequent to reopening of the occluded vessel. Initial reports of this treatment in experimental studies suggested that the method was easy and effective.2426 The first postconditioning report in humans9 showed a reduction in myocardial infarct size at MRI and an improved left ventricular ejection fraction, whereas a later similar proof-of-concept study4 found a reduction in infarct size adjusted for the area at risk but no effect on left ventricular function. In some smaller studies, no effect of postconditioning could be demonstrated on resolution of ST-segment elevation or MRI-based infarct measurements.14,26 The DANAMI-3–iPOST trial is, to our knowledge, the largest study to date and was powered to detect a reduction in clinical end points.

The neutral result of our primary end point is supported by findings of no difference in the surrogate end points of infarct size, myocardial salvage, microvascular obstruction, and resolution of ST-segment elevation, which are all well-established prognostic predictors.21,22 A meta-analysis of 10 randomized clinical trials concluded that postconditioning may confer cardioprotection with regard to enzyme leakage and left ventricular function and that this effect is more prone in younger patients.27 On the other hand, postconditioning might expand the infarct area.13 Several factors may play a role in the different results of these studies, of which the postconditioning algorithm is probably the most important. Many trials use 4 cycles of 1 minute of reperfusion followed by 1 minute of reocclusion.9,11,28 We chose 4 cycles of 30-second reperfusion followed by 30-second low-pressure balloon occlusion. This algorithm was previously used in a STEMI proof-of-concept study4 in which postconditioning increased myocardial salvage by 19% at MRI evaluation.

In general, the effect of postconditioning seems to be diminished in recent studies,8 which could reflect a general improvement in outcomes in patients with STEMI. That routine postconditioning failed in the present study may on the other hand suggest that some patients may respond to the therapy. An obvious limitation of postconditioning is the application of the conditioning therapy after reperfusion, suggesting that reperfusion injury occurs before any potential benefit of salvage therapy. Therefore, a different protocol in which postconditioning is instituted after a very short time of reperfusion (eg, 15 seconds) might be effective. Alternative strategies are remote ischemic conditioning29 and pharmacologic conditioning.30 In the study by Przyklenk et al,31 brief circumflex occlusions reduced infarct size from a subsequent sustained left anterior descendant occlusion in anesthetized dogs. Recently, Eitel et al15 reported an increase in myocardial salvage when remote conditioning was combined with postconditioning in STEMI. A similar effect of remote ischemic conditioning was reported in patients with STEMI by Bøtker et al29 and White et al32 using limb ischemia as the protective agent, and the results of another large trial are awaited.33

Reperfusion profiles in STEMI depend on several patient-related factors. These factors include time of ischemia, diabetic status, TIMI flow grade at admission, and antiplatelet therapy.34 The relatively low occurrence of diabetes was similar between our patient groups, and no interaction was found between diabetic status and treatment modality. Coronary blood flow in the infarct-related artery at admission was TIMI grade 0-1 flow. Lønborg et al35 reported a particularly large effect of the conditioning agent exenatide on myocardial salvage, infarct size, and left ventricular function in patients with STEMI and short duration of ischemia in comparison with that in patients who had a longer duration of ischemia. They suggested that reperfusion injury occurs with a stochastic incidence. Therefore, because the size of the insult from ischemia is profound after a long time, it may blunt any added component from reperfusion damage. Consequently, any assumed effect from a conditioning agent on reperfusion injury will therefore also be blunted. However, in the present study, we found no difference in the effect of postconditioning between patients with symptom duration of less vs more than 3 hours.

Limitations

We should note several limitations of the DANAMI-3–iPOST trial. First, the primary outcome was changed after inclusion of the last patient. This change was based on information from the event committee that separation of cardiac death from cardiovascular death was difficult. However, the adjustment was made before closing the database and before any knowledge or analysis of the data. Second, PCI operators were not blinded to the allocated treatment, and bias can therefore not be excluded. However, all subsequent data analysis was performed by study personnel blinded to study-group assignment. Third, inclusion of patients was not confined to patients with large anterior infarcts, who probably carry the worst prognosis. In that context, any effect on a clinical hard end point may be blunted by the smaller infarcts. Finally, MRI was only performed in a subset of patients and may thus result in selection bias to MRI variables.

Conclusions

In the DANAMI-3–iPOST trial, routine postconditioning in addition to primary PCI failed to reduce the primary composite outcome of all-cause death and hospitalization for heart failure. Whether postconditioning may offer cardioprotection in an enriched STEMI population remains unknown.

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Article Information

Corresponding Author: Thomas Engstrøm, MD, Department of Cardiology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, Copenhagen 2100, Denmark (thomas.engstroem@regionh.dk).

Accepted for Publication: January 4, 2017.

Published Online: March 1, 2017. doi:10.1001/jamacardio.2017.0022

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Author Contributions: Dr Engstrøm had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Engstrøm, Kelbæk, Helqvist, Clemmensen, Holmvang, S. E. Jensen, Treiman, Lønborg, Køber.

Acquisition, analysis, or interpretation of data: Engstrøm, Kelbæk, Helqvist, Høfsten, Kløvgaard, Clemmensen, Jørgensen, Pedersen, Saunamaki, Ravkilde, Tilsted, Villadsen, Aarøe, S. E. Jensen, Raungaard, Bøtker, Terkelsen, Maeng, Kaltoft, Krusell, L. O. Jensen, Veien, Kofoed, Torp-Pedersen, Kyhl, Nepper-Christensen, Vejlstrup, Ahtarovski, Lønborg, Køber.

Drafting of the manuscript: Engstrøm, Helqvist, Kløvgaard, Aarøe.

Critical revision of the manuscript for important intellectual content: Engstrøm, Kelbæk, Helqvist, Høfsten, Clemmensen, Holmvang, Jørgensen, Pedersen, Saunamaki, Ravkilde, Tilsted, Villadsen, S. E. Jensen, Raungaard, Bøtker, Terkelsen, Maeng, Kaltoft, Krusell, L. O. Jensen, Veien, Kofoed, Torp-Pedersen, Kyhl, Nepper-Christensen, Treiman, Vejlstrup, Ahtarovski, Lønborg, Køber.

Statistical analysis: Engstrøm, Helqvist, Høfsten, Nepper-Christensen, Lønborg, Køber.

Obtained funding: Engstrøm, Kelbæk, Køber.

Administrative, technical, or material support: Engstrøm, Kelbæk, Helqvist, Høfsten, Kløvgaard, Clemmensen, Holmvang, Villadsen, S. E. Jensen, Raungaard, Bøtker, Krusell, Veien, Kofoed, Kyhl, Nepper-Christensen, Vejlstrup, Ahtarovski, Køber.

Study supervision: Engstrøm, Kelbæk, Helqvist, Clemmensen, Holmvang, Jørgensen, Saunamaki, Villadsen, S. E. Jensen, Terkelsen, Lønborg, Køber.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Engstrøm reports receiving fees from Boston Scientific, St Jude Medical, AstraZeneca, and Bayer. Dr Clemmensen reports fees/grants from Medtronic, Eli Lilly, Daiichi-Sankyo, AstraZeneca, Bayer, Boehringer-Ingelheim, Sanofi, Pfizer, and BMS. Dr L.O. Jensen reports fees/grants from St Jude Medical, Biotronic, and Biosensors. Dr Pedersen reports fees/grants from Novo, Biotronic, Bristol-Myers Squibb, Sanofi, and Bayer. Dr Køber reports receving fees from Servier. No other disclosures were reported.

Funding/Support: This study was supported by grant 09-066994 from the Danish Agency for Science, Technology, and Innovation and Danish Council for Strategic Research.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The following investigators participated in the Third Danish Study of Optimal Acute Treatment of Patients With ST Elevation Myocardial Infarction–Ischemic Postconditioning (DANAMI-3–iPOST): Kristian Thygesen, DMSc, Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (chairman); Jørgen Jeppesen, DMSc, Department of Medicine, Copenhagen University Hospital Glostrup, Copenhagen, Denmark; Anders Galløe, PhD, Department of Cardiology, Roskilde Hospital, Roskilde, Denmark (clinical events committee); Gorm Boje Jensen, DMSc, Department of Cardiology, Hvidovre Hospital, Hvidovre, Denmark (chairman); Gunnar Gislasson, PhD, Department of Cardiology, Gentofte Hospital, Cohenhagen, Denmark; and David Erlinge, DMSc, Department of Cardiology, Lund University, Lund, Sweden (data safety monitoring board).

Additional Contributions: We thank our patients for their willingness to participate in the trial despite their acute condition at inclusion and the coinvestigators, our colleagues, and the staff of the participating centers, including our dedicated research nurses.

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