Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: A randomized controlled clinical trial

International Journal of Cardiology 177 (2014) 935–941

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Intracoronary injection of adenosine before reperfusion in patients with ST-segment elevation myocardial infarction: A randomized controlled clinical trial☆ David Garcia-Dorado a,⁎,1, Bruno García-del-Blanco a,1, Imanol Otaegui a,1, José Rodríguez-Palomares a,1, Victor Pineda b,1, Federico Gimeno c,1, Rafael Ruiz-Salmerón d,1, Jaime Elizaga e,1, Arturo Evangelista a,1, Francisco Fernandez-Avilés e,1, Alberto San-Román c,1, Ignacio Ferreira-González a,f,1 a

Cardiology Department, Vall d'Hebron Hospital, Universitat Autónoma de Barcelona, Barcelona, Spain Institute for Diagnostic Imaging (IDI), Vall d'Hebron Hospital, Barcelona, Spain c Institute for Heart Science (ICICOR), Clinic University Hospital of Valladolid, Valladolid, Spain d Cardiology Department, University Hospital Virgen de la Macarena, Seville, Spain e Cardiology Department, University General Hospital Gregorio Marañón , Department of Cardiology, Madrid, Spain f Research Center for Epidemiology and Public Health of the Carlos III Health Institute (CIBERESP), Spain b

a r t i c l e

i n f o

Article history: Received 28 May 2014 Received in revised form 16 September 2014 Accepted 30 September 2014 Available online 7 October 2014 Keywords: Reperfusion injury Infarct size Infarct remodeling Adenosine

a b s t r a c t Background: The effect of intracoronary adenosine (ADO) on ST-segment elevation myocardial infarction (STEMI) size and adverse remodeling is not well established. Methods: In a double-blind trial, 201 patients with STEMI were randomized to receive percutaneous coronary intervention (PCI) within 6 hours of symptom onset, 4.5 mg ADO or saline immediately prior to reperfusion. Primary end-point: percentage of total myocardial necrotic mass by cardiac magnetic resonance (CMR) 2–7 days post-reperfusion. Secondary end-points: changes in left ventricular volumes and ejection fraction (LVEF) at baseline and at 6 months. Results: Baseline CMR could not be performed in 20 patients. Overall, no significant differences were observed between ADO and placebo regarding infarct size (20.8% vs. 22.5%; p = 0.40). However, infarct size was significantly reduced (19.4% vs. 25.7%; p for interaction = 0.031) in those with ischemia duration below the median (200 min). CMR at 6 months, performed in 138 patients, did not show statistically significant differences between groups in the rate of LVEF increase (3.3 units (SD 9.6) in ADO group vs. 1.5 units (SD 9) in placebo group; p = 0.25). In the subgroup analysis, among patients with ischemia time below 200 min, the increase in LVEF was slightly higher with ADO (3.59% vs. 0.43%; p for interaction = 0.06). Conclusions: Although our study failed to demonstrate that intracoronary administration of ADO prior to PCI limits infarct size, in patients receiving early PCI ADO might enhance myocardial salvage and has a favorable effect on LVEF evolution, which may help to reconcile apparently contradictory results of previous studies. Clinical trial registration: http://clinicaltrials.gov (NCT00781404). © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Although reperfusion therapy has improved survival in patients with acute ST-segment elevation myocardial infarction (STEMI) [1], it does not prevent the occurrence of significant myocardial necrosis

☆ Funding: This work was supported by The Carlos III Institute of Health, Ministry of Science, Spain, grant number EC07/90511 and RETICS RD06/0014/0025. ⁎ Corresponding author at: Cardiology Department, Vall d'Hebron Hospital, Paseig Vall d'Hebron 119-129, 08035, Barcelona, Spain. Tel.: +34 932746134; fax: +34 932746063. E-mail address: [email protected] (D. Garcia-Dorado). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

http://dx.doi.org/10.1016/j.ijcard.2014.09.203 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

and, eventually, adverse left ventricular remodeling and heart failure in the majority of cases [2–4]. Based on extensive preclinical studies, a number of clinical trials aimed at identifying therapies able to limit infarct size in patients with STEMI have been conducted [5]. The ability of adenosine to protect against myocardial ischemiareperfusion injury has been extensively studied in laboratory models and also in patients with STEMI, with unclear initial results that were not translated to clinical practice [6]. More recently, adenosine was shown to induce protective signaling in cardiomyocytes, involving both nitric oxide and protein kinase G (PKG) [7–9]. The ability of intracoronary adenosine infusion immediately before coronary stenting to limit infarct size has been tested in clinical trials with disappointing results [10–12]. A proof-of-concept study in patients with STEMI

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receiving primary percutaneous coronary intervention (PCI) within 4 hours of symptom onset suggested a protective effect [10] although a larger, more recent study showed discrepant results [11]. However, both studies differed not only in size, but also in critical aspects of their design, such as ischemia duration and TIMI flow at the time of PCI, which render their results difficult to compare. Patients in the Marzilli study received reperfusion during the first 3 hours of ischemia versus 12 hours in the Desmet trial [10]. Only TIMI flow grade 0–1 was included in the Marzilli study vs. 0–3 in the Desmet trial. The present trial was designed to determine whether an intracoronary injection of adenosine immediately prior to coronary artery recanalization limits infarct size and prevents adverse remodeling in patients with STEMI receiving PCI within 6 hours of symptom onset and with TIMI flow grade 0–I. In a pre-specified subgroup analysis we additionally hypothesized, that the ability of adenosine to limit infarct size is greater in patients receiving PCI earlier after symptom onset than in those receiving it later.

delineating the enhanced areas in the late enhancement sequences, with 5 standard deviations above average, obtained from the remote healthy myocardium, and normalized by the left ventricular mass. The hypoenhanced areas, considered as microvascular obstruction, were included in the infarct volume. All CMR measurements were taken by experienced researchers unaware of the study group assignment. Details of the CMR procedures are given in the appendix.

2. Methods

The primary outcome was a comparison of superiority between adenosine and placebo regarding infarct size as determined by late enhancement on CMR. Infarct size in the control group was calculated to reach 15 grams. It was estimated that, with 100 patients per group, the study would have 80% power to show statistical superiority of a reduction of 4 grams (26.7%) considering a type I error of 0.05. Baseline characteristics and procedural data for the two trial groups were compared by Student's t-test for continuous variables and the chi-square test or Fisher's exact test for categorical variables, where appropriate. In the same manner, primary and secondary outcomes were compared with the use of Student's t-test. Analyses were made following the intention-to-treat principle modified. Therefore, only patients in each group who had received the assigned study treatment were considered for the analysis. Baseline and follow-up CMR could not be performed in all randomized patients. It was decided to analyze the primary and secondary outcomes in all patients with CMR and not impute the missing outcome data in patients without CMR. Finally, the changes in primary and secondary outcomes between baseline and follow-up CMR were analyzed by the paired t-test. Study of the adenosine effect on the percentage of total necrotic mass as a function of ischemia duration was included as a pre-specified subgroup analysis and it was hypothesized that the effect of adenosine would be greater in patients with shorter ischemia time. No formal sample size was computed for this specific hypothesis. A post-hoc subgroup analysis concerning the involvement of the left anterior descending artery was also explored. The potential different effect of ADO depending on the corresponding subgroup was explored by the interaction test. No interim analyses or stopping rules were defined for the present study.

2.1. Study design and oversight The PROMISE (protection with adenosine during primary PCI in patients with STEMI) clinical trial was a multicenter, randomized, parallel, placebo-controlled, double-blind trial conducted at five sites in Spain. Adenosine was purchased, and the manufacturers had no role in the study. The study protocol was approved by the Ethics Committees of all participating institutions. All patients gave their written informed consent. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee 2.2. Study participants Eligible patients were over 18 years of age with a diagnosis of STEMI on ECG and receiving PCI within 6 hours of symptom onset. Exclusion criteria were previous myocardial infarction and TIMI flow grade 1 on initial angiography. Patients with potential contraindications for adenosine (bronchospastic lung disease) were excluded, as were those with contraindications for MRI examination or for gadolinium administration (renal function b30 mL/min/1.73 m2) or those with life-expectancy of less than 6 months. 2.3. Study treatment and procedures Coronary angiography and PCI procedures were performed at the operator's discretion following international PCI guidelines. For a patient to be deemed eligible, the culprit artery had to show an initial TIMI 0 or I in antegrade flow, and remain lower than III once the guidewire had crossed to the distal bed. Once the study investigator confirmed that TIMI flow remained II or lower after crossing the lesion with the guidewire to the distal bed, study participants were randomly assigned, at a 1:1 ratio, to receive 10 mL saline with or without 4.5 mg adenosine. This adenosine dose had been found to be protective in an earlier pilot study [10]. The randomization sequence was performed in permuted block sizes of 5 and 5. The investigator who performed the procedure was at all times blinded to the study medication. The study medication was administered as a 2-minute intracoronary bolus distal to the culprit lesion by means of an intracoronary infusion microcatheter (AMI cath® Iberhospitex, Lliçà de Vall, Spain) or an OTW coaxial balloon, once the wire had been withdrawn and without dilating the balloon itself. Thereafter, direct stenting was recommended, but thrombectomy or balloon predilatation prior to stent deployment were left to the operator's discretion. Concomitant non-culprit lesions were not treated per protocol in the index procedure (unless cardiogenic shock during PCI not responding to culprit lesion angioplasty occurred). Sum ST was calculated upon patient arrival to the cath lab and at the end of the procedure as the sum of ST-segment elevations in all ECG leads related to the infarct location. Complete ST resolution was defined as a reduction larger than 70% in sum ST between both measurements. 2.4. Cardiac magnetic resonance Cardiac magnetic resonance studies were performed with 1.5 Tesla equipment (Siemens; Avanto). Short-axis cine views were performed to quantify volumes and ejection fraction. Additional 2-chamber, 3-chamber, and 4-chamber views were also obtained. Late enhancement sequences were acquired at identical slice positions as the cine images and were used to quantify the size of the myocardial infarction. They were obtained 10 min after intravenous administration of 0.2 mmol/kg of dimegluminegadopentetate (Magnevist). All studies were conducted on a workstation (QMASS MR 7.2, Medis Medical Imaging Systems, The Netherlands). Endocardial and epicardial borders were delineated at end-systole and end-diastole with short-axis views to quantify volumes, function and left ventricle mass. Quantification of the infarcted myocardium was assessed by

2.5. Outcomes and follow-up The primary outcome was infarct size measured as total myocardial necrotic mass as determined by late enhancement on CMR imaging performed between 2 and 7 days postreperfusion. Secondary outcomes were differences between groups in ejection fraction and ventricular volumes on the baseline CMR, in ejection fraction, infarct size and ventricular volumes on the CMR performed at 6 months, and the difference between groups in creatine-kinase MB peak at the index episode. Follow-up assessments were made at the hospital 6 months after the index hospitalization and they included a standardized CMR performed according to the protocol. Potential adverse outcomes were assessed by study investigators not involved in the treatment of patients and unaware of the treatment assignment. 2.6. Statistical analysis

3. Results 3.1. Study participants From October 2008 to May 2011, 201 patients were randomized to receive adenosine (101 patients) or placebo (100 patients) (Fig. 1). One patient in the adenosine group and three in the placebo group did not eventually receive the therapy. Median time interval between symptom onset and TIMI III flow was 200 min (inter-quartile range: 160–255). No significant differences were observed between groups concerning baseline clinical and angiographic characteristics (Table 1). Coronary TIMI 3 flow could be achieved in 179 (90.9%) patients. Complete ST-segment resolution at the end of the procedure was observed in 55.1% and 65.5% of patients in the placebo and adenosine groups respectively (p = 0.18). 3.2. Baseline outcomes Initial CMR was performed in 177 patients: 91 in the adenosine and 86 in the placebo groups. CMR was not performed in 20 patients owing to death (n = 4), claustrophobia (n = 6), refused informed consent (n = 1) or other causes mostly related to availability of the technique (n = 9) (Fig. 1). Overall no significant differences were found between groups in the percentage of total necrotic myocardial mass as determined by enhancement on CMR (20.8 (SD 12.2) vs. 22.5 (SD 14.0); p = 0.4) (Fig. 2A). Neither were there significant differences regarding secondary outcomes such as creatine kinase-MB serum levels (301.1 vs. 286

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937

Fig. 1. Flow chart of the study.

units; p = 0.56), left ventricular ejection fraction (49.5% vs. 49.4%), ventricular volumes, area of microvascular obstruction and the infarct transmurality index (Table 2). No serious adverse events were related to adenosine (Table S1 in the appendix). Two patients experienced complete atrio-ventricular block, both in the adenosine group (one during injection of the drug and another at the end of the procedure). In both cases the block was transient and did not require pacing.

and placebo groups, respectively (p = 0.84). Changes in the remaining CMR parameters within each group from baseline to 6 months of follow-up and differences between study groups are shown in Table 3. The percentage of myocardial necrotic mass was reduced in both groups; however, neither the magnitude of reduction nor the final figures differed between groups.

3.3. Follow-up outcomes

A more pronounced effect of adenosine was observed in patients with ischemia duration less than the median value (b 200 min) regarding the percentage of total necrotic mass (19.4% (SD 11.4%) vs. 25.7% (SD 17%); p for interaction 0.031) (Fig. 2C and Table S2 in the appendix). In addition, ejection fraction recovery tended to be higher with adenosine in this subgroup of patients (Fig. 2D), with the ejection fraction at 6 months being somewhat higher with adenosine (53.8% (SD 11.17) vs. 50.01% (SD 11.31); p for interaction 0.06) (Table S2). A trend towards

Follow-up was completed in 180 patients, and a second CMR study could be performed in 74 in the adenosine group and 64 in the placebo group (Fig. 1). An increase in ejection fraction from baseline to 6 months was found in both groups (Fig. 2B). The final ejection fraction did not differ between groups (52.1% (SD 11.2%) vs. 51.7% (SD 10.5%)) in adenosine

3.4. Pre-specified subgroup analyses: duration of ischemia

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Table 1 Baseline clinical characteristics according to study group a.

Age (years) (mean(SD)) Gender (females) (n, %) Hypertension (n, %) Current smoker (n, %) Hyperlipidemia (n, %) Diabetes (n, %) Body mass indexb (mean(SD)) Pre-infarction angina (n, %) Killip class at presentation (n, %) I II III–IV Creatinine at presentation (mg/dL) (mean(SD)) Systolic blood pressure at presentation (mm Hg) (mean(SD)) Heart rate at presentation (mean(SD)) Time symptom-onset-hospital-arrival (min) Time hospital-arrival-maximum TIMI flow (mean(SD)) Intra-procedure data Radial vascular access (n, %) Number of coronary arteries affected (n, %) One vessel Two vessels Three vessels Culprit lesion at proximal left anterior coronary artery (n, %) TIMI coronary flow at the first coronary angiography (n, %) 0 1 Rentrop collateral coronary flow (n, %) None Secondary branches Main coronary artery Thrombectomy (n, %) Bare stent implantation (n, %) Glycoprotein IIb–IIIa inhibitor administration (n, %) Final TIMI coronary flow (n, %) 1 2 3 Final myocardial Blush Grade (n, %) 0 1 2 3 Time symptom-onset maximum TIMI coronary flow (min) a b

Placebo (n = 97)

Adenosine (n = 100)

Total (n = 197)

N

N

N

97 97 97 97 97 97 97 86 97

96 97 97 96 94 97 97

97 97

58.6 (13.9) 12 (12.4) 45 (46.4) 54 (55.0) 29 (29.9) 12 (12.4) 28.1 (3.58) 15 (17.4) 75 (77.3) 16 (16.5) 6 (6.3) 0.92 (0.25) 123.8 (23.7) 74.7 (5.1) 158.3 (64.4) 54.4 (37.5) 84 (86.6)

100 100 100 100 100 100 99 91 100

97 100 100 99 96 100 100

59 (60.8) 29 (29.9) 9 (9.3) 31 (32)

100 100

93 (95.9) 4 (4.12)

88 (88) 58 (58) 28 (28) 14 (14) 28 (28)

100 54 (55.7) 32 (33) 11 (11.3) 75 (77.3) 86 (88.7) 65 (67)

100 100 100

1 (1.0) 11 (11.3) 85 (87.6)

193 197 197 195 190 197 197

197 197

96

159 (80.71) 23 (11.68) 15 (7.62) 0.92 (0.25) 124.8 (25.9) 74.2 (7.2) 153.9 (70.3) 54.6 (35.3) 172 (87.3) 117 (59.4) 57 (28.9) 23 (11.7) 59 (30)

197 45 (45) 35 (35) 20 (20) 73 (73) 82 (82) 63 (63)

94 7 (7.4) 8 (8.4) 27 (28.4) 53 (55.8) 213.9 ± 63.1

59.21 (13.0) 27 (13.7) 92 (46.7) 102 (51.8) 60 (30.5) 30 (15.2) 28.1 (3.52) 28 (15,8)

0.98 0.64 0.37 0.27 0.60 0.77 0.59

0.54 0.39

197 197 197

0.17 99 (50.3) 67 (34) 31 (15.7) 148 (75.1) 168 (85.3) 128 (65.3)

0.48 0.19 0.62 0.26

2 (1.0) 16 (8.1) 179 (90.9) 189

5 (5.3) 7 (7.4) 20 (21.3) 62 (65.9) 208 ± 72.4

0.43 0.59 0.93 0.05 0.87 0.27 0.96 0.80 0.10

191 (96.9) 6 (3.05%)

1 (1.0) 5 (5) 94 (94)

95

94

84 (84) 7 (7) 9 (9) 0.92 (0.24) 125.87 (27.9) 73.7 (19.0) 149.6 (75.7) 54.8 (33.3)

197 197 197 197 197 197 196 177 197

98 (98) 2 (2%)

97

97 97 97 97

59.8 (12.2) 15 (15) 47 (47) 48 (48) 31 (31) 18 (18) 28.1 (3.47) 13 (14.9)

p

190

0.54 12 (6.3) 15 (7.9) 47 (24.9) 115 (60.8) 210.3 ± 67.9

0.27

Plus–minus values are means ± SD. Body-mass index: weight in kilograms divided by the square of height in meters.

lower Ck-MB peak values was also found in the adenosine group of this subgroup of patients (247 (SD 158) vs. 314 (SD 167) units; p for interaction 0.12) (Table S2). There was also a non-significant trend towards a higher rate of ST-segment resolution in these patients as compared to those receiving placebo (66.0% and 46.9% respectively, p = 0.09) 3.5. Infarct localization, pre-infarction angina and TIMI flow grade No effect was apparent in other subgroup analyses regarding involvement of the left anterior coronary artery (Table S2). Sixteen percent of patients included in the study had presented preinfarction angina. These patients could have been preconditioned and adenosine could have been less effective in them. In fact, the effect of adenosine tended to be more pronounced when these patients were excluded from the analysis, with an absolute difference of 2.8% in infarct size in the global study population (P = 0.25), and of 7.7% (30% reduction, P = 0.026) in the subgroup of patients with duration of ischemia shorter than 200 min (Table S3). Similarly, in patients with TIMI flow grade = 2 after crossing the lesion with the guidewire to the distal bed, reperfusion injury could have already taken place when adenosine was administered. However, exclusion of these patients did not modify the results (Table S3).

4. Discussion This study failed to demonstrate a protective effect of the intracoronary administration of adenosine before reperfusion in patients with STEMI receiving PCI. However, it did suggest a potential beneficial effect of this treatment on infarct size in patients receiving PCI earlier after symptom onset. Our data also suggest that intracoronary adenosine before PCI may have a beneficial effect on the evolution of LVEF following STEMI. In initial clinical trials assessing the usefulness of adenosine in STEMI, the drug was administered intravenously during the hours following reperfusion [13,14]. Although the AMISTAD I and II trials, involving more than 2300 patients, indicated an infarct-sparing effect of intravenous adenosine when administered at high doses, the main results of those trials were consistent in demonstrating no beneficial effect of adenosine on adverse cardiovascular events. However, a posthoc sub-analysis of AMISTAD II suggested a benefit of adenosine within the first 3.17 hours onset of evolving anterior ST-segment elevation AMI [15]. The use of intracoronary adenosine in patients with STEMI receiving PCI was first proposed by a pilot study showing a reduction in angiographic “no reflow” and improved left ventricular segment contraction

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A)

B)

C)

D)

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Fig. 2. Percentage of baseline total necrotic mass and change in left ventricular ejection fraction during follow-up in the study groups in the whole population (upper panel) and in the subgroup of patients with time-onset symptom TIMI III flow less than 200 min (lower panel). In the whole population, no significant differences were observed between groups in the percentage of total necrotic myocardial mass (p = 0.4) (A), although the increase in left ventricular ejection fraction during follow-up was significant with adenosine(p = 0.006) but not with placebo (B) (p = 0.25). In the subgroup of patients with time-onset symptom TIMI III flow less than 200 min, the percentage of baseline total necrotic mass was lower in the adenosine group (C) (p for interaction = 0.031) and the recovery of ejection fraction was also greater with adenosine (p for interaction = 0.06). Δ: mean increase in ejection fraction from baseline to 6 months of follow-up.

in 54 patients with STEMI of less than 3 hours evolution [10]. The protective effect of adenosine was reproduced in a subsequent angiographic study in 70 patients receiving PCI within 6 hours of symptom onset in which myocardial blush grade was measured [16] and recently in the RE-OPEN randomized open-label trial [12]. In the latter, 80 patients receiving intracoronary adenosine at the time of PCI showed less angiographic microvascular obstruction and lower peak myocardial necrosis biomarkers than those receiving placebo. However, these promising results were not reproduced in a trial involving 112 patients with STEMI in which no beneficial effect of intracoronary adenosine was observed on infarct size and on “no reflow” [11]. The present trial differed from previous studies in that it was significantly larger, included only patients with TIMI flow grade 0 or 1 at the time of PCI and a second CMR study was performed at 6 months in the majority of patients. Our results are partially consistent with the beneficial effect of adenosine observed in three trials [10,12,16] and with a post-hoc subanalysis of AMISTAD II trial [15], but apparently contradictory with the SALVAGE trial. Two important differences could explain these discrepancies. First, the SALVAGE trial included patients regardless of TIMI flow before PCI, and second, it included patients up to 12 hours after symptom onset. Since there is strong evidence that myocardial

reperfusion injury occurs from the initial minutes of reperfusion [5, 17], it is not surprising that treatments applied after flow restoration fail to prevent it. On the other hand, there is evidence indicating that reperfusion-induced myocardial salvage rapidly decreases after the first 90–120 min of ischemia [18,19]. After this time, the benefit of PCI is due to adverse remodeling reduction rather than to infarct size limitation [20], which is consistent with experimental observations in large mammals [21,22]. It is thus conceivable that additional infarct size limitation by prevention of reperfusion injury may be more difficult after longer periods of ischemia. Moreover, there is evidence that the mechanisms responsible for reperfusion-induced cell death may differ according to the duration of ischemia [23]. While inhibition of mitochondrial permeability transition by cyclosporine or postconditioning may be effective after a prolonged ischemic period, treatments that are able to reduce sarcoplasmic reticulum-driven calcium oscillations and hypercontracture appear to be more effective after shorter ischemic periods [23]. Increased nitric oxide availability and PKG signaling induced by adenosine [9] are expected to act via this mechanism. Finally, pre-clinical studies suggest that cardioprotective effect of anti-platelet therapy might mask any protection from a conditioning agent like adenosine [24,25]. If so was the case the potential differences between

Table 2 Secondary study outcomes in the index episodea.

End-diastolic volume (mL) (mean(SD)) End-systolic volume (mL) (mean(SD)) Left ventricular ejection fraction (%) (mean(SD)) Microvascular obstruction volume (%) Infarct transmurality index Creatine kinase-MB peak (mcg/L) BSA: body surface area. a Plus–minus values are means ± SD.

Placebo (n = 86)

Adenosine (n = 91)

Total (n = 177)

N

N

N

86 86 86 86 84 86

149.7 (36.6) 76.7 (27.8) 49.4 (10.2) 2.9 (5.3) 64.2 (12.9) 301.1 (172.2)

91 91 91 91 90 91

155.7 (34.8) 80.2 (29.7) 49.5 (10.4) 2.7 (5.0) 63.5 (13.4) 286 (176.5)

177 177 177 177 174 177

152.8 (35.7) 78.2 (8.7) 49.4 (10.3) 2.8 (5.1) 63.9 (13.1) 293.3 (174.1)

p

0.27 0.42 0.96 0.85 0.72 0.56

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Table 3 Study outcomes at 6 months and differences from baseline valuesa.

Percentage of total necrotic myocardial mass (%) (mean(SD)) Difference 6 months-baseline p Value for the difference Tele-diastolic volume (mL) (mean(SD)) Difference 6 months-baseline p Value for the difference Tele-diastolic volume indexed by BSA (mean(SD)) Difference 6 months-baseline p Value for the difference Tele-systolic volume (mL) (mean(SD)) Difference 6 months-baseline p Value for the difference Tele-systolic volume indexed by BSA (mean(SD)) Difference 6 months-baseline p Value for the difference Ejection fraction (%) (mean(SD)) Difference 6 months-baseline p Value for the difference Infarct transmurality index (mean(SD)) Difference 6 months-baseline p Value for the difference a

Placebo (n = 64)

Adenosine (n = 74)

N

N

64 64 64 64 64 64 64 64 64 64 64 64 63 61

21.2 (13.7) −1.2 (14.0) 0.48 164.7 (46.6) 14.3 (31.1) b0.001 85.8 (2.7) 7.5 (15.8) b0.001 81.6 (38.5) 5.7 (24.2) 0.029 42.6 (9.4) 3 (12.3) 0.030 51.7 (10.5) 1.5 (9) 0.25 61.5 (13.7) 1.9 (13.9) 0.22

74 74 74 74 74 74 74 74 74 74 74 74 73 72

19.7 (11.8) −0.9 (7.4) 0.31 167.4 (42.1) 11.9 (33.2) 0.005 88.1 (21.3) 6.8 (19.3) 0.005 83.6 (36.8) 2.7 (26.2) 0.577 44.1 (19.9) 1.7 (14.5) 0.59 52.1 (11.2) 3.3 (9.6) 0.006 63.3 (16.2) 0.0 (18.2) 0.82

P

0.49 0.85 0.72 0.65 0.54 0.82 0.75 0.49 0.66 0.59 0.84 0.25 0.45 0.49

Plus–minus values are means ± SD.

studies concerning anti-platelet use could partially explain the heterogeneity of the effect of adenosine. As a primary endpoint we used infarct size instead of the myocardial salvage index employed in other studies [11]. Having observed the potential application of T2-weighted images to detect myocardial edema and outline the area at risk after treatment for coronary occlusion [26], we were aware of the limitations of this measurement, as other authors recently pointed out [27]. In addition, the potential effect of cardioprotective intervention on myocardial edema [28] could bias estimation of the area at risk. Therefore, we decided to employ infarct size as a more accurate and robust primary endpoint to assess the effect of the intervention. The potential association between adenosine and an increase in ejection fraction during the ensuing 6 months appeared to be clearer in patients with less than 200 min of ischemia. This potential effect does not appear to be explicable by a reduction in infarct size. Rather it could be related to a limitation in the area of microvascular obstruction in CMR, since there was a non-significant trend towards less microvascular obstruction in the adenosine group. In fact, areas of microvascular obstruction have been shown to correspond to zones of microvascular destruction and interstitial hemorrhage [29], and are associated with altered healing and adverse remodeling [30]. Our study had several limitations. The actual infarct size in the whole sample and, especially, the actual standard deviation were higher than those initially expected, thereby reducing the power of the study. Although the analysis of the subgroup of patients with shorter ischemia duration was pre-specified in the study design, sample size was not powered for this specific subgroup analysis. On the other hand, primary and secondary outcomes could not be assessed in patients without CMR study, which could have introduced some bias into our results. However, a detailed analysis showed no great differences in baseline clinical and angiographic characteristics between patients with and without CMR (Table S4 in the appendix). Thus, although the possibility of bias remains, it is unlikely to have changed the main findings of the study. Finally, the average improvement in LVEF over the 6-month follow-up observed in patients receiving adenosine, albeit statistically significant, was small. In conclusion, our results are concurrent with previous studies in showing that intracoronary administration of adenosine immediately before reperfusion does not limit infarct size in the general population of patients with STEMI receiving PCI. However, our results indicate

that this safe and inexpensive treatment might limit infarct size and improve recovery of LVEF during the months following STEMI in patients receiving PCI early after symptom onset. Although the magnitude of these effects is probably modest in the overall STEMI population, they may be important since the extent of necrosis and LVEF are major determinants of the prognosis. The dependence of adenosine effect on ischemic time showed in this trial may help to reconcile the apparently discrepant results of previous studies. Clinical trials aimed at assessing the effect of intracoronary adenosine on clinical outcomes of patients receiving PCI early after symptom onset are required. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.09.203. References [1] White HD, Chew DP. Acute myocardial infarction. Lancet 2008;372(9638):570–84. [2] Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert Y, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med 2013;368(15):1379–87. [3] Terkelsen CJ, Sorensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S, et al. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA 2010;304(7):763–71. [4] Terkelsen CJ, Jensen LO, Tilsted HH, Trautner S, Johnsen SP, Vach W, et al. Health care system delay and heart failure in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: follow-up of population-based medical registry data. Ann Intern Med 2011;155(6):361–7. [5] Hausenloy DJ, Erik BH, Condorelli G, Ferdinandy P, Garcia-Dorado D, Heusch G, et al. Translating cardioprotection for patient benefit: position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2013;98(1):7–27. [6] Forman MB, Stone GW, Jackson EK. Role of adenosine as adjunctive therapy in acute myocardial infarction. Cardiovasc Drug Rev 2006;24(2):116–47. [7] Yang Z, Sun W, Hu K. Molecular mechanism underlying adenosine receptormediated mitochondrial targeting of protein kinase C. Biochim Biophys Acta 2012; 1823(4):950–8. [8] Kin H, Zatta AJ, Lofye MT, Amerson BS, Halkos ME, Kerendi F, et al. Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res 2005;67(1):124–33.

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