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Coronary artery disease
Original research
Interaction of ischaemic postconditioning and thrombectomy in patients with ST-elevation myocardial infarction
  1. Lars Nepper-Christensen1,
  2. Dan Eik Høfsten1,
  3. Steffen Helqvist1,
  4. Jens Flensted Lassen1,
  5. Hans-Henrik Tilsted1,
  6. Lene Holmvang1,
  7. Frants Pedersen1,
  8. Francis Joshi1,
  9. Rikke Sørensen1,
  10. Lia Bang1,
  11. Hans Erik Bøtker2,
  12. Christian Juhl Terkelsen2,
  13. Michael Maeng2,
  14. Lisette Okkels Jensen3,
  15. Jens Aarøe4,
  16. Henning Kelbæk5,
  17. Lars Køber1,
  18. Thomas Engstrøm1,
  19. Jacob Lønborg1
  1. 1 Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
  2. 2 Department of Cardiology, Aarhus University Hospital Skejby, Aarhus, Denmark
  3. 3 Department of Cardiology, Catheterisation Lab, Odense University Hospital, Odense, Denmark
  4. 4 Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
  5. 5 Department of Cardiology, Roskilde University Hospital, Roskilde, Denmark
  1. Correspondence to Dr Lars Nepper-Christensen; lars.nepper{at}gmail.com

Abstract

Objective The Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction – Ischaemic Postconditioning (DANAMI-3-iPOST) did not show improved clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI) treated with ischaemic postconditioning. However, the use of thrombectomy was frequent and thrombectomy may in itself diminish the effect of ischaemic postconditioning. We evaluated the effect of ischaemic postconditioning in patients included in DANAMI-3-iPOST stratified by the use of thrombectomy.

Methods Patients with STEMI were randomised to conventional primary percutaneous coronary intervention (PCI) or ischaemic postconditioning plus primary PCI. The primary endpoint was a combination of all-cause mortality and hospitalisation for heart failure.

Results From March 2011 until February 2014, 1234 patients were included with a median follow-up period of 35 (interquartile range 28 to 42) months. There was a significant interaction between ischaemic postconditioning and thrombectomy on the primary endpoint (p=0.004). In patients not treated with thrombectomy (n=520), the primary endpoint occurred in 33 patients (10%) who underwent ischaemic postconditioning (n=326) and in 35 patients (18%) who underwent conventional treatment (n=194) (adjusted hazard ratio (HR) 0.55 (95%confidence interval (CI) 0.34 to 0.89), p=0.016). In patients treated with thrombectomy (n=714), there was no significant difference between patients treated with ischaemic postconditioning (n=291) and conventional PCI (n=423) on the primary endpoint (adjusted HR 1.18 (95% CI 0.62 to 2.28), p=0.62).

Conclusions In this post-hoc study of DANAMI-3-iPOST, ischaemic postconditioning, in addition to primary PCI, was associated with reduced risk of all-cause mortality and hospitalisation for heart failure in patients with STEMI not treated with thrombectomy.

Trial registration number NCT01435408.

  • percutaneous coronary intervention
  • acute coronary syndromes
  • acute myocardial infarction

https://doi.org/10.1136/heartjnl-2019-314952

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    Introduction

    Progress in medical and interventional strategies have dramatically improved outcome in patients presenting with ST-segment elevation myocardial infarction (STEMI).1 2 However, even when treated with timely primary percutaneous coronary intervention (PCI)3 the 1 year mortality rate after STEMI is still above 10%.4 Despite the obvious benefits from restoration of myocardial blood flow by primary PCI, reperfusion per se may jeopardise the myocardium. This is known as reperfusion injury and accounts for up to 50% of the total myocardial damage5; preventing this phenomenon may further improve outcomes in STEMI.

    Ischaemic postconditioning is a technique where final reperfusion of the infarct-related artery is preceded by repetitive brief interruptions of the blood flow during the early phase of reflow.6 Several experimental models have reported that this technique protects the heart against reperfusion injury with reduction in myocardial damage.6 7 Although proof-of-concept studies demonstrated cardioprotective effects of ischaemic postconditioning8–10 the largest randomised trial evaluating ischaemic postconditioning (the Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction – Ischaemic Postconditioning (DANAMI-3-iPOST)) failed to confirm these results.11 However, in the DANAMI-3-iPOST trial, a non-significant trend in event rate favoured ischaemic postconditioning. In accordance with guidelines at the time the trial was conducted, the use of thrombectomy was frequent. Early initiation of ischaemic postconditioning – within 30 to 60 s after reperfusion – is pivotal to avoid or reduce reperfusion injury. Therefore initial thrombectomy, postponing re-occlusion of the vessel in itself, may inhibit the cardioprotective effects of ischaemic postconditioning.12 Following several randomised clinical trials, the routine use of thrombectomy has since been downgraded in guidelines.3 Thus, it may be speculated that the benefit of ischaemic postconditioning in the DANAMI-3-iPOST trial was blunted by the frequent use of thrombectomy and that ischaemic postconditioning may improve outcome in patients who are not treated with thrombectomy.

    In this analysis of DANAMI-3-iPOST, we compared the effect of ischaemic postconditioning on the primary endpoint of all-cause mortality and hospitalisation for heart failure in STEMI patients treated with and without thrombectomy respectively.

    Methods

    Study design and participants

    This is a post hoc analysis of DANAMI-3-iPOST, an open-label randomised controlled trial, which was conducted at the four primary PCI centres in Denmark. The results of the main trial and the trial protocol has been published.11 13 In brief, it was part of the DANAMI-3 programme; a multicentre clinical trial evaluating revascularisation strategies in STEMI patients (ischaemic postconditioning (DANAMI-3-iPOST),11 deferred stenting (DANAMI-3-DEFER)14 and complete revascularisation (DANAMI-3- PRIMULTI).15

    Patients with STEMI ≥18 years of age presenting ≤12 hours of symptom onset with thrombolysis in myocardial infarction (TIMI) flow 0/1 on the initial angiogram were eligible. STEMI was defined as acute onset of 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 electrocardiography. Unconsciousness, cardiogenic shock, stent thrombosis, indication for acute coronary artery bypass surgery and intolerance to antithrombotic medication, contract media or anticoagulants constituted major exclusion criteria.

    All participants 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 at each of the recruiting hospitals approved the study protocol before initiation of the trial. All data was prospectively collected and electronically stored at the Clinical Trial Unit of Rigshospitalet, Copenhagen University Hospital, Denmark.

    Randomisation and procedures

    In DANAMI-3-iPOST, patients were randomly allocated (1:1) to primary PCI plus ischaemic postconditioning or conventional primary PCI alone by the time of angiography. Randomisation was performed via an electronic web-based system using the permuted block method, with varying block sizes.13 The invasive PCI team performed enrolment and randomisation, and had no further involvement in the subsequent assessment or treatment of the patients. In the present analysis, patients were grouped according to the use of thrombectomy and stratified by randomised treatment.

    It was aimed to perform ischaemic postconditioning within 60 s after reopening of the infarct related artery and before stent implantation. After securing a TIMI flow of 2 or 3 by wire insertion or by dilation with an undersized balloon, a semi-compliant balloon sized to obstruct the vessel was inflated for 30 s at a pressure of four to eight atmospheres and subsequently deflated for 30 s. This cycle of ischaemic postconditioning (30 s of obstructed blood flow followed by 30 s of reperfusion) was repeated four times. Intracoronary nitroglycerine was standard therapy in all patients, while the use of thrombectomy, as well as bivalirudin and/or glycoprotein IIb/IIIa inhibitors was left at the decision of the operator. All additional treatment was performed in accordance with contemporary guidelines. At the discretion of the operator thrombectomy was allowed before reperfusion and postconditioning.

    Outcomes

    The primary endpoint was the same as in DANAMI-3-iPOST, a composite of all-cause mortality and hospitalisation for heart failure. Cardiovascular death constituted a secondary endpoint. Hospitalisation for heart failure was defined as prolongation of the index hospitalisation due to worsening of existing heart failure, development of heart failure after the primary PCI or later presentation to an acute care facility that required at least 6 hours of hospitalisation with an exacerbation of heart failure requiring treatment.11 All endpoints were identified using national registries and validated by an independent clinical events committee. An independent safety monitoring board reviewed all adverse event reports; no severe adverse effects related to ischaemic postconditioning were observed.11

    Statistical analysis

    Continuous variables were tested for normality and student’s t-test or Mann-Whitney U test was used as appropriate. Dichotomous data are presented as frequencies and percentages, and were compared using X2 or Fisher’s exact test. Kaplan-Meier curves, cumulative incidence curves and log-rank tests are used to present survival probabilities. Hazard ratios were calculated using Cox proportional hazards regression analyses and a test for interaction between ischaemic postconditioning and thrombectomy in the total DANAMI-3-iPOST cohort on the primary endpoint was performed. To adjust for potential confounders a multivariable survival analysis was performed adjusting for age, sex, diabetes mellitus, previous myocardial infarction, anterior infarct location that are known to be associated with outcome among patients with STEMI3 and any other baseline variables with a p value<0.1 for a difference between the treatment groups. In addition, the multivariable analyses were repeated adjusting for variables with a p value<0.1 for the difference between patients who were and were not treated with thrombectomy regardless of randomisation. The assumption of the Cox proportional hazards regression models were tested by plot of cumulative sum of martingale-based residuals16 and found valid. No interactions between any variable included in the multivariable models and ischaemic postconditioning on the effect of the primary endpoint were identified unless otherwise stated. As all patients included in the DANAMI-3 trial programme could be randomised to complete or culprit-only revascularisation in DANAMI-3-PRIMULTI interaction between ischaemic postconditioning and this second treatment on the primary endpoint was tested. All analyses were performed using SPSS software V.23.0 (SPSS Inc, Chicago, Illinois) and R V.3.3.2 (R development core team). A p value<0.05 was considered statistically significant for all analyses.

    Results

    From 21 March, 2011, through 2 February, 2014, 1234 patients were included in DANAMI-3-iPOST of which 714 were treated with thrombectomy and 520 did not undergo thrombectomy. In patients not treated with thrombectomy, 326 patients were randomised to ischaemic postconditioning and 194 were randomised to conventional primary PCI. The numbers were 291 and 423 in patients treated with thrombectomy (figure 1). Baseline patient characteristics, PCI procedural data and medication at discharge are shown in table 1 and table 2. Except for glycoprotein IIb/IIIa inhibitors, which were more frequently used in the ischaemic postconditioning group, the two treatment groups were well-balanced in patients not treated with thrombectomy. In patients treated with thrombectomy, with the exception of the number of implanted stents and medical therapy at discharge, the groups were likewise well balanced.

    Figure 1
    Figure 1

    Patient inclusion. DANAMI-3-iPOST, the Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction – Ischaemic Postconditioning; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; TIMI, thrombolysis in myocardial infarction.

    View this table:
    Table 1

    Baseline characteristics, PCI procedural data and medical therapy at discharge in patients who were not treated with thrombectomy stratified by treatment

    View this table:
    Table 2

    Baseline characteristics, PCI procedural data and medical therapy at discharge in patients treated with thrombectomy stratified by treatment

    The median follow-up period was 35 months (interquartile range 28 to 42). There was a significant interaction between the use of thrombectomy and ischaemic postconditioning on both the primary clinical endpoint (p=0.004), and all-cause mortality (p=0.004). In patients not treated with thrombectomy, the primary endpoint occurred in in 33 patients (10%) who underwent ischaemic postconditioning and in 35 patients (18%) who underwent conventional treatment. Event rates are shown in table 3. Ischaemic postconditioning was associated with a reduced risk of both the primary endpoint (HR 0.50 (95% confidence interval (CI) 0.31 to 0.81), p=0.005 and all-cause mortality (HR 0.35 (95% CI 0.19 to 0.64), p<0.001) (Figures 2,3 and table 4). There was a non-significant numerical reduction in heart failure (HR 0.55 (95% CI 0.28 to 1.11), p=0.095) (Figure 4 and table 4). No difference was observed between the patients randomised to ischaemic postconditioning or conventional treatment among patients treated with thrombectomy (Figures 2-4 and table 4). The association between ischaemic postconditioning and the primary endpoint remained statistically significant in a multivariable model adjusting for age, sex, diabetes mellitus, previous myocardial infarction, anterior infarct location and glycoprotein IIb/IIIa inhibitor (HR 0.55 (95% CI 0.34 to 0.89), p=0.016) (table 4). The association between ischaemic postconditioning and all-cause mortality also remained statistically significant in a multivariate model adjusting for the same factors as stated above (HR 0.41 (95% CI 0.22 to 0.75), p=0.004) (table 4). In patients treated with thrombectomy, there was no significant association between ischaemic postconditioning and the primary endpoint in either univariate or multivariate models (HR 1.37 (95% CI 0.85 to 2.32), p=0.19 and HR 1.18 (95% CI 0.62 to 2.28), p=0.62) (table 4). In patients not treated with thrombectomy, the secondary outcome of cardiovascular death occurred less often in patients who underwent ischaemic postconditioning compared with patients treated with conventional primary PCI (HR 0.34 (95% CI 0.15 to 0.74), p=0.007) (table 3). There was no difference in event rates in patients treated with thrombectomy (HR 1.67 (95% CI 0.82 to 3.43), p=0.16) (table 3).

    View this table:
    Table 4

    The association between ischaemic postconditioning and outcome stratified by use of thrombectomy

    Figure 4
    Figure 4

    Cumulative incidence curves of hospitalisation for heart failure stratified by randomised treatment in DANAMI-3-iPOST patients without (A) and with (B) prior thrombectomy.

    Figure 2
    Figure 2

    Kaplan-Meier curves of the combined primary endpoint stratified by randomised treatment in DANAMI-3-iPOST patients without (A) and with (B) prior thrombectomy.

    Figure 3
    Figure 3

    Kaplan-Meier curves of all-cause mortality stratified by randomised treatment in DANAMI-3-iPOST patients without (A) and with (B) prior thrombectomy.

    View this table:
    Table 3

    Event rates stratified by randomised treatment in patients treated with and without thrombectomy

    Significant differences between patients who were and were not treated with thrombectomy were observed (online supplementary eTable 1). In patients not treated with thrombectomy, the association between ischaemic postconditioning and the primary endpoint remained statistically significant when including all variable with a p value<0.1 for the difference in the multivariable analysis (HR 0.55 (95% CI 0.32 to 0.93), p=0.03). In patients treated with thrombectomy, the association between ischaemic postconditioning and the primary endpoint remained insignificant (HR 1.24 (95% CI 0.70 to 2.18), p=0.46).

    Supplemental material

    In patients treated with thrombectomy, 23 patients (12%) in the conventional group underwent full revascularisation and 47 (14%) in the ischaemic postconditioning group underwent full revascularisation (p=0.42). There was no interaction between complete revascularisation and ischaemic postconditioning on the primary endpoint (p=0.46). Of patients treated with thrombectomy, 50 patients (48%) in the conventional group and 28 (44%) in the ischaemic postconditioning group underwent full revascularisation (p=0.63); there was no interaction between full revascularisation and ischaemic postconditioning on the primary endpoint (p=0.45).

    Discussion

    In this post hoc analysis of DANAMI-3-iPOST, four cycles of ischaemic postconditioning were significantly associated with a reduced risk of a combined endpoint of all-cause mortality and hospitalisation for heart failure in STEMI patients presenting with TIMI flow 0/1 pre-PCI treated with primary PCI without prior thrombectomy. However, since this is a post hoc analysis of an overall neutral study these findings need to be confirmed in a prospective study. Nevertheless, this is the first trial to show a possible cardioprotective effect of ischaemic postconditioning on clinical endpoints in patients with STEMI. The effect was a substantial 65% relative risk reduction of all-cause mortality, and these promising cardioprotective effects of ischaemic postconditioning should thus continue to be pursued. We are currently awaiting the results of the Ischaemic Postconditioning in STEMI Patients Treated with Primary PCI (iPOST2) trial (ClinicalTrials.gov Identifier: NCT03787745).

    Several clinical trials evaluated the potential cardioprotective effects of ischaemic postconditioning on surrogate endpoints and reported conflicting results.8–10 17 18 Early trials showed a significant reduction in myocardial damage and improvement of left ventricular function,8–10 while more recent studies could not confirm these findings.17 18 It has been suggested that the effect of ischaemic postconditioning is simply blunted by the general improvement of interventional and medical treatments in STEMI during the last couple of decades.11 These improvements do not include use of routine thrombectomy, which has changed dramatically through the era of primary PCI.19 20 Importantly, the use of thrombectomy may impede the cardioprotective effects of ischaemic postconditioning,12 and major differences in the use of thrombectomy are observed when comparing trials of ischaemic postconditioning. Thrombectomy was used in less than 20% of the patients included in a study by Lønborg et al 8 and was not used at all by Staat and colleagues.9 Both reported beneficial effects of ischaemic postconditioning. In contrast, thrombectomy was used in more than 45% of the patients included in trials reporting neutral effects17 18 and in approximately 60% of participants in the parent DANAMI-3-iPOST trial.11 In this context, it should be realised that the foundation of reperfusion injury is laid immediately after reopening of the coronary artery.5 Initial thrombectomy may hamper the effect of ischaemic postconditioning by delaying this intervention enough to result in irreversible reperfusion injury21 and subsequent ischaemic postconditioning is simply initiated too late in these instances to have a cardioprotective effect. Alternatively thrombectomy mimic the cardioprotective effects of ischaemic postconditioning by a slow restoration of total coronary blood flow.22 Furthermore, manipulation of the thrombus may loosen thrombotic material causing distal embolisation and occlusion of the microvascular circulation23 and diminishing all following attempts of mechanical cardioprotection.

    The fact that the use of thrombectomy was left at the discretion of the PCI operator, and the number of patients treated with thrombectomy was unbalanced between the randomisation groups, could confound our results, as the risk profile of the treatment groups could potentially be unbalanced. However, our analysis of patients who underwent thrombectomy stratified by randomised treatment revealed only minor differences and randomised treatment had no statistical impact on the primary or the secondary endpoints. In addition, PCI operators may primarily have used thrombectomy in patients with high thrombus burden that could be expected to benefit the most from the treatment or alternatively they may have avoided thrombectomy in patients who were randomised to postconditioning. Event rates in the thrombectomy group per se were low, but importantly, the decision of thrombectomy did not impact randomisation in the present study. The possibility that treatment with thrombectomy resulted in better outcome, as indicated by the lower event rates in these patients, and that subsequent treatment with ischaemic postconditioning could not provide any beneficial effects beyond those achieved by thrombectomy is attractive. However, as large-scale clinical trials found no beneficial effects of thrombectomy, regardless of the size of the thrombus burden19 20 it seems unlikely that the difference in clinical outcome between the patients included in the present study was caused by beneficial effects of thrombectomy. Furthermore, our results remained consistent when performing multivariable adjustments.

    Limitations

    Patients were not randomised to thrombectomy and thrombectomy was more frequently used in patients randomised to conventional PCI, underlining the previous mentioned risk of excluding high-risk conventionally treated patients. Additionally, it would have been interesting to present data on the thrombus burden in the culprit lesion, but data is unfortunately not available. Finally, as the present trial is a post hoc analysis and thus only hypothesis generating by nature, large-scale randomised clinical trials to confirm these promising results of ischaemic postconditioning are warranted.

    Conclusion

    In this post hoc analysis of DANAMI-3-iPOST, ischaemic postconditioning in addition to primary PCI reduced the risk of all-cause mortality and hospitalisation for heart failure in patients who were not treated with thrombectomy. Given the post hoc nature of the study this finding is considered hypothesis generating, but the results are intriguing and warrant further evaluation in large-scale randomised clinical trials to settle the true impact of ischaemic postconditioning in patients with STEMI.

    Key messages

    What is already known on this subject?

    • Previous clinical trials on ischaemic postconditioning during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) reported conflicting results. The initially promising results of ischaemic postconditioning may have been negated by routine use of thrombectomy, which is no longer recommended by guidelines.

    What might this study add?

    • In this post hoc analysis of the Third Danish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction – Ischaemic Postconditioning, we showed that ischaemic postconditioning during primary PCI reduced the risk of all-cause mortality and hospitalisation for heart failure substantially compared with conventional primary PCI in patients with STEMI not treated with thrombectomy (33 patients (10%) vs 35 patients (18%) (adjusted HR 0.55 (95% CI 0.34 to 0.89), p=0.016)).

    How might this impact on clinical practice?

    • The results presented herein suggest that the promising cardioprotective effects of ischaemic postconditioning should continue to be pursued. We are currently awaiting the results of the Ischaemic Postconditioning in STEMI Patients Treated with Primary PCI (iPOST2) trial (ClinicalTrials.gov Identifier: NCT03787745).

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    Footnotes

    • TE and JL contributed equally.

    • Contributors Planning: TE, JL, LN-C, LK, SH, HK Conduct: All. Reporting: All. Overall responsible: TE.

    • Funding This work was supported by the Danish Agency for Science, Technology and Innovation, and the Danish Council for Strategic Research (Eastern Denmark Initiative to Improve Revascularisation Strategies (EDITORS), grant 09-066994).

    • Competing interests LK reports grants from Danish Research Foundation during the conduct of the study. TE reports personal fees from Boston Scitienfic, Abbott, Bayer, Novo Nordisk and Astra Zeneca outside the submitted work.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice Since this paper was first published online, Henning Kelbæk’s affiliation has been updated.

    • Patient consent for publication Not required.

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