In patients with ST-segment elevation myocardial infarction (STEMI), ischemic postconditioning (iPOST) have shown ambiguous results in minimizing reperfusion injury. Previous findings show beneficial effects of iPOST in patients with STEMI treated without thrombectomy. However, it remains unknown whether the cardioprotective effect of iPOST in these patients persist on long term. In the current study, all patients were identified through the DANAMI-3-iPOST database. Patients were randomized to conventional primary percutaneous coronary intervention (PCI) or iPOST in addition to PCI. Cumulative incidence rates were calculated, and multivariable analyses stratified according to thrombectomy use were performed. The primary end point was a combination of cardiovascular mortality and hospitalization for heart failure. From 2011 to 2014, 1,234 patients with STEMI were included with a median follow-up of 4.8 years. In patients treated without thrombectomy (n = 520), the primary end point occurred in 15% (48/326) in the iPOST group and in 22% (42/194) in the conventional group (unadjusted hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41 to 0.94, p = 0.023). In adjusted Cox analysis, iPOST remained associated with reduced long-term risk of cardiovascular mortality (HR 0.53, 95% CI 0.29 to 0.97, p = 0.039). In patients treated with thrombectomy (n = 714), there was no significant difference between iPOST (17%, 49/291) and conventional treatment (17%, 72/423) on the primary end point (unadjusted HR 1.01, 95% CI 0.70 to 1.45, p = 0.95). During a follow-up of nearly 5 years, iPOST reduced long-term occurrence of cardiovascular mortality and hospitalization for heart failure in patients with STEMI treated with PCI but without thrombectomy.
Treatments and reperfusion strategies of patients with ST-segment elevation myocardial infarction (STEMI) have improved and become more preventive of adverse complications after STEMI, yet additional myocardial injury may occur immediately after restoration of coronary blood flow and may account for up to 50% of the damage to myocardium, a phenomenon called reperfusion injury. Thus, ischemic postconditioning (iPOST) by repetitive brief interruptions of blood flow before establishment of final reperfusion, has demonstrated ambiguous results in minimizing reperfusion injury. Our group previously published the Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction (DANAMI-3-iPOST) trial assessing the effect of iPOST during primary percutaneous coronary intervention (PCI) versus conventional PCI alone on the primary composite outcome of all-cause mortality and hospitalization for heart failure in patients with STEMI. Although iPOST failed to reduce the primary end point, a post hoc analysis showed that iPOST reduced short-term risk of all-cause mortality and hospitalization for heart failure in patients who were not treated with thrombectomy. Therefore, we performed an analysis of the long-term prognostic impact of iPOST in patients with STEMI treated with and without thrombectomy.
The DANAMI-3 trial was an open-label, randomized controlled trial evaluating 3 different revascularization strategies in patients with STEMI: iPOST (DANAMI-3-iPOST), deferred stenting (DANAMI-3-DEFER), and complete revascularization (DANAMI-3-PRIMULTI). Details of the study design, patient selection, and exclusion criteria have been described previously. , , This long-term study of the DANAMI-3-iPOST trial included 1,234 consecutive patients with STEMI ≥18 years. Patients were admitted to 1 of the 4 primary PCI centers in Denmark between March 2011 to February 2014 with ≤12 hours of symptom onset with thrombolysis in myocardial infarction flow 0/1 in culprit vessel on the initial angiogram. STEMI was defined as acute chest pain with <12 hours of duration and ST-segment elevation ≥0.1 mV in ≥2 contiguous leads or documented newly developed left bundle branch block on electrocardiogram.
All data on included patients were retrieved from the DANAMI-3-iPOST database. It holds information on clinical, angiographic, and procedural characteristics including prescriptions and co-morbidities before STEMI admission. The database was linked through a unique civil registration number to Danish nationwide administrative registries. The personalized and permanent civil registration number assigned to all Danish residents allow unambiguous and individual linkage between all nationwide registries. Vital status was retrieved from the Civil Registration Registry. Based on death certificates according to the International Classification of Diseases, Eighth and Tenth Revisions (ICD-8 and ICD-10), the cause of death was retrieved from the National Causes of Death Registry which holds information on time of death and both the primary and contributing causes of death. Information on hospitalization for heart failure after STEMI admission was collected from the National Patient Registry according to ICD-10 Code I42, I50, I110, I130, I132, or J819, or ICD-8 Code 425, 428, 4,270, 4,271.
All patients were randomly allocated to either conventional PCI or iPOST in connection with PCI. Thrombectomy was performed at the discretion of the invasive cardiologist. The primary end point of this study was a combination of cardiovascular mortality and hospitalization for heart failure. Secondary outcomes were the individual components of the primary outcome and all-cause mortality. Owing to a long follow-up, we included cardiovascular mortality as a component of the primary outcome because noncardiac mortality such as malignancies or lung diseases are responsible for the majority of deaths on long-term following STEMI. Cardiovascular mortality was defined as a secondary end point in the original DANAMI-3-iPOST trial. In the initial follow-up, identification of outcomes was done by using national registries and checked by an event committee. , Following the initial follow-up, the identification was done by national registries and ICD-8 and ICD-10 codes for heart failure and cardiovascular mortality (Supplementary Table 1). The follow-up period ran until the occurrence of the outcome of interest, noncardiovascular mortality, date of emigration, or study end (December 31, 2017).
Continuous variables were tested for normality, presented as mean (SD) or median and interquartile range, and compared using t test or Mann-Whitney’s U tests, as appropriate. Categoric variables presented as frequencies and percentages were compared using the chi-square test or Fisher’s exact test. Cumulative incidence was calculated taking the competing risk of death from other causes into account. Gray’s test was used to compare groups. Both unadjusted and adjusted hazard ratio (HR) and 95% confidence interval (CI) were calculated by Cox proportional hazard analysis, and a test for interaction between iPOST and thrombectomy in the total DANAMI-3-iPOST cohort on the primary and secondary end points was performed. Multivariate Cox models were adjusted for age, gender, and use of glycoprotein IIb/IIIa inhibitor. Interaction between iPOST and age, gender, and use of glycoprotein IIb/IIIa inhibitor was tested on the primary end point. In patients with multivessel disease, interaction between iPOST and treatment with either complete or culprit-only revascularization was tested on the primary outcome, as these patients could secondarily be randomized in DANAMI-3-PRIMULTI. Furthermore, the assumptions for proportional hazard and linearity for numeric values were tested and found valid. Finally, additional analyses investigating event rates and interaction between iPOST and the primary end point were performed for certain subgroups. A 2-sided p value ≤0.050 was considered statistically significant in all analyses. Analyses were performed using SAS (version 9.4, SAS Institute Inc, Cary, North Carolina) and R Core Team (2020). All participants in the DANAMI-3-iPOST trial (ClinicalTrials.gov Identifier NCT01435408) provided oral and written informed consent before initiation of any trial-related treatment. The trial was performed in accordance with the Declaration of Helsinki, and a local ethics committee and an institutional review board approved the study protocol before initiation of the trial. This present study was approved by the Danish Data Protection Agency (2007‐58‐0015/GEH‐2014‐014 and I‐suite number: 02732). In Denmark, register-based studies in anonymous setup do not require ethical approval.
The study population has been described previously. Among 1,234 DANAMI-3-iPOST included patients with STEMI, 714 underwent thrombectomy (57.9%) and 520 did not (42.1%). Baseline characteristics are presented in Table 1 . The median follow-up time was 4.8 (interquartile range 4.2 to 5.50) years.
| No thrombectomy | Thrombectomy | |||||
|---|---|---|---|---|---|---|
| Conventional(n = 194) | iPOST(n = 326) | p Value | Conventional(n = 423) | iPOST(n = 291) | p Value | |
| Demographics | ||||||
| Age, years | 64 ± 12 | 63 ± 11 | 0.28 | 60 ± 12 | 62 ± 11 | 0.10 |
| Male | 145 (75%) | 75 (77%) | 0.59 | 341 (81%) | 238 (82%) | 0.70 |
| Comorbid and clinical conditions | ||||||
| Hypertension | 77 (40%) | 137 (42%) | 0.58 | 132 (32%) | 104 (36%) | 0.22 |
| Hyperlipidemia | 58 (30%) | 93 (29%) | 0.77 | 123 (30%) | 80 (28%) | 0.61 |
| Diabetes mellitus | 18 (9%) | 30 (9%) | >0.99 | 32 (8%) | 25 (9%) | 0.67 |
| Active or previous smoker | 145 (75%) | 246 (76%) | 0.75 | 332 (79%) | 218 (76%) | 0.27 |
| Family history of CAD | 82 (44%) | 136 (44%) | >0.99 | 175 (44%) | 119 (42%) | 0.75 |
| Previous myocardial infarction | 11 (6%) | 17 (5%) | 0.84 | 25 (6%) | 13 (5%) | 0.50 |
| Previous PCI or CABG | 15 (8%) | 16 (5%) | 0.25 | 24 (6%) | 16 (6%) | >0.99 |
| Symptoms onset to PCI, hours | 2.8 (2.0-4.9) | 3.0 (2.2-4.9) | 0.29 | 3.0 (2.2-4.8) | 2.8 (2.1-4.4) | 0.24 |
| Killip class II-IV at any time | 14 (7%) | 13 (4%) | 0.15 | 35 (8%) | 20 (7%) | 0.57 |
| LVEF at discharge, % | 50 [40; 55] | 45 [40; 50] | 0.06 | 50 [40; 55] | 45 [40; 55] | 0.24 |
| Peak CKMB, * µg/L | 156 [73; 258] | 187 [92; 317] | 0.07 | 217 [114; 320] | 237 [118; 337] | 0.38 |
| Intervention | ||||||
| Culprit vessel | ||||||
| Right coronary artery | 92 (47%) | 136 (42%) | 0.38 | 194 (46%) | 137 (47%) | 0.48 |
| Left main artery | 0 (0%) | 0 (0%) | 0 (0%) | 1 (0%) | ||
| Left anterior descending artery | 69 (36%) | 135 (41%) | 176 (42%) | 123 (43%) | ||
| Circumflex artery | 33 (17%) | 55 (17%) | 53 (13%) | 29 (10%) | ||
| Pre-PCI operator-reported TIMI flow 0-1 | 194 (100%) | 326 (100%) | >0.99 | 423 (100%) | 291 (100%) | 0.47 |
| Post-PCI operator-reported TIMI flow 3 | 181 (93%) | 312 (96%) | 0.20 | 400 (95%) | 276 (95%) | 0.63 |
| Multivessel disease | 87 (45%) | 149 (46%) | 0.86 | 161 (38%) | 100 (36%) | 0.34 |
| Procedure-related medicine | ||||||
| Use of glycoprotein IIb/IIIa inhibitor | 13 (7%) | 40 (12%) | 0.051 | 55 (13%) | 49 (17%) | 0.16 |
| Use of bivalirudin | 156 (80%) | 265 (81%) | 0.82 | 347 (82%) | 240 (83%) | 0.92 |
| Medical therapy at discharge | ||||||
| Antiplatelet therapy | ||||||
| Aspirin | 188 (97%) | 321 (99%) | 0.19 | 413 (98%) | 284 (98%) | >0.99 |
| Clopidogrel | 30 (16%) | 35 (11%) | 0.13 | 69 (17%) | 57 (20%) | 0.27 |
| Prasugrel or ticagrelor | 161 (84%) | 290 (89%) | 347 (83%) | 228 (80%) | ||
| Statin | 185 (96%) | 316 (97%) | 0.45 | 417 (99%) | 281 (97%) | 0.06 |
| β-blocker | 161 (83%) | 285 (87%) | 0.19 | 383 (91%) | 264 (91%) | >0.99 |
| ACE inhibitor or angiotensin II receptor blocker | 93 (48%) | 161 (50%) | 0.79 | 193 (46%) | 162 (56%) | 0.010 |
| Calcium channel blocker | 26 (13%) | 35 (11%) | 0.40 | 20 (5%) | 20 (7%) | 0.25 |
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