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Abstract
Objective We investigated influence of remote ischaemic conditioning (RIC) on the detrimental effect of healthcare system delay on myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI).
Methods A post-hoc analysis of a randomised controlled trial in patients with STEMI randomised to treatment with pPCI or RIC+pPCI. RIC was performed as four cycles of intermittent 5 min upper arm ischaemia and reperfusion. Healthcare system delay was defined as time from emergency medical service call to pPCI-wire. Myocardial salvage index (MSI) was assessed by single photon emission computerised tomography.
Results Data for healthcare system delay and MSI were available for 129 patients. MSI was negatively associated with healthcare system delay in patients treated with pPCI alone (−0.003 decrease in MSI/min of healthcare system delay; 95% CI −0.005 to −0.001, r2=0.11, p=0.008) but not in patients treated with RIC+pPCI (−0.0002 decrease in MSI/min of healthcare system delay; 95% CI −0.001 to 0.001, r2=0.002, p=0.74). In patients with healthcare system delay ≤120 min, RIC+pPCI did not affect median MSI compared with pPCI alone (0.75 (IQR: 0.49–0.99) and 0.70 (0.45–0.94), p=1.00). However, in patients with healthcare system delay >120 min, RIC+pPCI increased median MSI compared with pPCI alone (0.74 (0.52–0.93) vs 0.42 (0.22–0.68), p=0.02). Adjusting for potential confounders did not affect the results.
Conclusions RIC as adjunctive to pPCI attenuated the detrimental effect of healthcare system delay on myocardial salvage in patients with STEMI, suggesting that the cardioprotective effect of RIC increases with the duration of ischaemia.
Trial registration number NCT00435266; post-results.
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Introduction
In ST-segment elevation myocardial infarction (STEMI), rapid restoration of blood flow is crucial in order to salvage ischaemic myocardium. Even with updated prehospital diagnostics, triage,1 and reperfusion strategies including primary percutaneous coronary intervention (pPCI) or thrombolysis,2 the current in-hospital mortality varies between 3% and 14% depending on the country of origin and method of reperfusion strategy.3 While short-term survival from STEMI has markedly improved, long-term survival has been less favourably influenced,4 mainly due to postinfarction heart failure,5 leaving a need for further improvements.
A major challenge in treatment of patients with STEMI is the inevitable healthcare system delay, that is, the time from first medical contact to reperfusion. Healthcare system delay is negatively associated with myocardial salvage, infarct size, left ventricular function6 and clinical outcome7 ,8 in patients with STEMI treated with pPCI. For patients with STEMI referred for pPCI, current European guidelines recommend a healthcare system delay of ≤120 min from emergency medical service call.2
Remote ischaemic conditioning (RIC) has emerged as a promising adjunctive therapy to protect the myocardium against ischaemia–reperfusion injury.9 Induced by short-term intermittent periods of ischaemia and reperfusion of the upper arm, RIC increases myocardial salvage and reduces infarct size in patients with STEMI treated with pPCI10–12 or thrombolysis,13 and may translate into improved long-term clinical outcome.14 The aim of the present study was to evaluate the influence of RIC on the unfavourable consequence of healthcare system delay on myocardial salvage in patients with STEMI undergoing pPCI.
Methods
Study design and participants
We conducted a post-hoc analysis of a single-centre, single-blinded, randomised controlled trial.10 The study protocol and patient randomisation have previously been described in detail.10 The present study included all per-protocol analysis patients from the parent trial, that is, all randomised patients fulfilling inclusion criteria and with available follow-up data for myocardial salvage index (MSI). Briefly, a total of 333 patients were enrolled between February 2007 and November 2008. Criteria for inclusion were: (1) age ≥18 years, (2) duration of symptoms ≤12 h prior to hospital admission and (3) ST-segment elevation ≥0.1 mV in two or more contiguous electrocardiogram leads. Exclusion criteria were: (1) diagnosis not confirmed upon arrival to the hospital, (2) history of previous myocardial infarction and (3) history of previous coronary artery bypass surgery.
Patients with a tentative diagnosis of STEMI were randomised in the ambulance to standard treatment with pPCI alone (n=167) or pPCI with prior application of RIC (n=166). RIC was initiated in the ambulance during transport to the hospital, and performed using a standard blood pressure cuff as four cycles of intermittent 5 min upper arm ischaemia and reperfusion. Prior to coronary catheterisation, patients were pretreated with aspirin 300 mg orally or intravenously, clopidogrel 600 mg orally and unfractionated heparin 10 000 IU intravenously. During pPCI procedure and the subsequent 12 h, patients were treated with abciximab intravenously unless contraindicated.
Study end points
The study end point was MSI on day-30 following pPCI as previously described in detail.10 MSI was assessed by single photon emission CT (SPECT). Briefly, prior to reperfusion therapy, patients received 700 MBq (±10%) of 99Technetium (99mTc)-sestamibi intravenously and SPECT was performed with a high-resolution parallel-hole collimator dual-headed rotating gamma camera (ADAC Laboratories, Forte, Milpitas, California, USA) within 8 h of injection to quantify myocardial area-at-risk of infarction. On day-30 following pPCI, a second SPECT scanning was performed 1 h after tracer injection to quantify final infarct size.
Using a well-validated method provided by the commercially available automatic programme Quantitative Perfusion SPECT (Cedars-Sinai Medical Center, Los Angeles, California, USA),15–17 all imaging data were analysed independently by two experienced nuclear cardiology readers blinded to treatment assignment and clinical data. Myocardial area-at-risk of infarction and final infarct size were determined as percentage of the left ventricle by calculating the area of the left ventricle containing lower counts than the normal mean limit for pixels using a sex-specific MIBIMIBI rest database. The nuclear cardiology readers performed a consensus reading when inter-reader difference of defect size exceeded 3%. By definition, MSI is the percentage of the ischaemic myocardium at risk being salvaged by the assigned treatment, and was calculated as: (area-at-risk−final infarct size)/area-at-risk. A MSI of 1 indicates maximum benefit from treatment, whereas a MSI of 0 indicates no benefit from treatment.
Healthcare system delay and data collection
Healthcare system delay was defined as time from emergency medical service call to pPCI-wire traversing the culprit lesion. Data were obtained from emergency medical service-related and pPCI-related registries and files. Patients with unavailable data for healthcare system delay were excluded from analysis. Additional analyses were conducted on treatment delay, defined as time from symptom onset to pPCI-wire traversing the culprit lesion.
The parent trial was conducted in accordance with the Declaration of Helsinki (2000) of the World Medical Association, and was approved by the local ethics committee, and registered with clinicaltrials.gov (NCT00435266). Written informed consent was obtained from all participants prior to inclusion.
Statistical analysis
Continuous variables were compared using Student's t test or Mann–Whitney U test for parametric and non-parametric data, respectively. Categorical variables were compared with χ2 test or Fisher's exact test. For patients with eligible data, multiple linear regression analysis was applied to identify independent predictors of MSI when adjusting for age, sex, healthcare system delay (per one min increase), preprocedural vessel patency (thrombolysis in myocardial infarction (TIMI) flow 0/1 vs TIMI flow 2/3), infarct related artery (left anterior descending artery vs non-left anterior descending artery) and treatment allocation (pPCI alone vs RIC+pPCI). We used simple linear regression analyses to evaluate the association between healthcare system delay and MSI, and treatment delay and MSI, for patients treated with pPCI alone or RIC+pPCI. Because MSI did not follow normal distribution in our subgroups, Dunn's multiple-comparison test with Bonferroni correction was used to evaluate difference in MSI between patients with a current guideline-recommended healthcare system delay of ≤120 min or >120 min and the effect of RIC.2 We added multiple linear regression analyses to adjust for potential confounding variables, that is, treatment allocation,10 infarct-related artery,10 preprocedural vessel patency,18 healthcare system delay6 and current smoking.19 If any other variable was found to be independent predictor of MSI or if any baseline characteristic variable with a p value of <0.05 in between treatment groups these were included in the multiple regression analysis. We justified the use of linear regression models by checking variance of error, the distribution of variance and a normal distribution of residuals prior to their application.
Data are expressed as mean with SD, number with percentages or median with IQR. For simple and multiple linear regression analyses, data are expressed as regression coefficient with 95% CI and r2 value when appropriate. Statistical significance was set as two-sided p value of <0.05.
The software STATA/SE V.13 (StataCorp, College Station, Texas, USA) and GraphPad PRISM 6 (GraphPad Software, La Jolla, California, USA) were used for statistical analysis.
Results
Baseline characteristics
Of the 333 patients initially enrolled in the parent trial, 251 patients were eligible for trial imaging follow-up and 140 patients had data for MSI. One patient was excluded from data analysis because of reinfarction between first and second SPECT scan resulting in unreliable MSI data. A total of 129 patients (pPCI alone n=63 and RIC+pPCI n=66) had eligible data for both MSI and healthcare system delay (figure 1). A guideline-recommended healthcare system delay of ≤120 min was achieved for a total of 80 patients (62%). Healthcare system delay of ≤120 min and >120 min was observed in 42 and 21 patients treated with pPCI alone, and in 38 and 28 patients treated with RIC+pPCI, respectively. Baseline characteristics and procedural variables did not differ between treatment groups, and application of RIC did not affect healthcare system delay. Data for treatment delay were available for a total of 125 patients (pPCI alone n=59 and RIC+pPCI n=65) with no difference between treatment groups (table 1).
Baseline characteristics and procedural data
Study flow chart. See Results section – Baseline characteristics, for details. pPCI, primary percutaneous coronary intervention; RIC, remote ischaemic conditioning; SPECT, single photon emission CT; MSI, myocardial salvage index.
Predictors of myocardial salvage
In a multiple regression analysis including adjustment for gender, age, preprocedural vessel patency, infarct-related artery and treatment allocation, healthcare system delay was an independent predictor of MSI and an extended healthcare system delay was negatively associated with MSI (−0.001 decrease in MSI/min of healthcare system delay; 95% CI −0.002 to −0.0001, p=0.028) implying that each additional hour of healthcare system delay decreased the salvaged myocardium by an estimated 6% (absolute) of the myocardium at risk. In the same statistical model, treatment with RIC+pPCI was the only other independent predictor of MSI (0.12 increase in MSI by RIC+pPCI compared with pPCI alone; 95% CI 0.02 to 0.22, p=0.02).
Effect of RIC on the detrimental effect of healthcare system delay on myocardial salvage
In a simple linear regression model, healthcare system delay was significantly associated with a reduction in MSI in patients treated with pPCI alone (−0.003 decrease in MSI/min of healthcare system delay; 95% CI −0.005 to −0.001, r2=0.11, p=0.008) but not in patients treated with RIC+pPCI (−0.0002 decrease in MSI/min of healthcare system delay; 95% CI −0.001 to 0.001, r2=0.002, p=0.74) (figure 2). In the same statistical model, we found a significant effect modification between healthcare system delay and RIC+pPCI on MSI (p=0.02), favouring the effect of RIC+pPCI with extended healthcare system delay. Similarly, treatment delay was significantly associated with a reduction in MSI in patients treated with pPCI alone (−0.0007 decrease in MSI/min of treatment delay; 95% CI −0.001 to −0.00004, r2=0.07, p=0.039) but not in patients treated with RIC+pPCI (−0.00007 decrease in MSI/min of treatment delay; 95% CI −0.0004 to 0.0003, r2=0.002, p=0.70) and with a borderline significant effect modification between treatment delay and RIC+pPCI on MSI (p=0.10).
Association between healthcare system delay and myocardial salvage index categorised according to patients treated with pPCI alone or RIC+pPCI. Data are regression line (solid) with 95% CI (dotted lines). p Values and r2 values are based on simple linear regression analysis. See text for details. pPCI, primary percutaneous coronary intervention; RIC, remote ischaemic conditioning.
In a multiple linear regression analysis adjusting for preprocedural vessel patency, infarct-related artery and current smoking, healthcare system delay remained negatively associated with MSI in patients treated with pPCI alone (−0.002 decrease in MSI/min of healthcare system delay; 95% CI −0.004 to −0.0002, p=0.03) but not in patients treated with RIC+pPCI (−0.001 decrease in MSI/min of healthcare system delay; 95% CI −0.002 to 0.001, p=0.26). In the same statistical model, a similar effect modification was observed between healthcare system delay and RIC+pPCI on MSI with statistically borderline significance (p=0.058).
Influence of healthcare system delay on the efficacy of RIC
Median MSI was lower in patients treated with pPCI and healthcare system delay >120 min than in patients with healthcare system delay ≤120 min (0.42 (IQR: 0.22–0.68) vs 0.70 (IQR: 0.45–0.94), p=0.03). However, median MSI did not differ in patients treated with RIC+pPCI and healthcare system delay >120 min compared with patients with healthcare system delay ≤120 min (0.74 (IQR: 0.52–0.93) and 0.75 (IQR: 0.49–0.99), p=1.00) (figure 3).
Effect of pPCI alone and RIC+pPCI on myocardial salvage index categorised according to patients with a healthcare system delay ≤120 min and >120 min. Data are box plot (25th percentile, median, and 75th percentile) with whisker (10th and 90th percentile). p Values are based on Dunn's multiple-comparison test with Bonferroni correction. See text for details. pPCI, primary percutaneous coronary intervention; RIC, remote ischaemic conditioning.
RIC+pPCI did not affect median MSI compared with pPCI alone in patients with healthcare system delay ≤120 min (0.75 (IQR: 0.49–0.99) and 0.70 (IQR: 0.45–0.94), p=1.00). RIC+pPCI significantly increased median MSI compared with pPCI alone in patients with healthcare system delay >120 min (0.74 (IQR: 0.52–0.93) vs 0.42 (IQR: 0.22–0.68), p=0.02). MSI for patients treated pPCI alone and healthcare system delay ≤120 min was similar to patients treated with RIC+pPCI and with healthcare system delay >120 min (0.70 (IQR: 0.45–0.94) and 0.74 (IQR: 0.52–0.93), p=1.00) (figure 3). In a simple linear regression model, effect modification between healthcare system delay ≤120 min or >120 min and RIC+pPCI on MSI favoured the effect of RIC+pPCI with healthcare system delay >120 min (p=0.049).
A multiple regression analysis adjusting for preprocedural vessel patency, infarct-related artery and current smoking did not change the results, as no difference in MSI was observed between pPCI alone and RIC+pPCI in patients with a healthcare system delay ≤120 min (0.03 increase in MSI from RIC+pPCI; 95% CI −0.10 to 0.16, p=0.64). However, MSI was higher from RIC+pPCI than pPCI alone in patients with a healthcare system delay >120 min (0.22 increase in MSI from RIC+pPCI; 95% CI 0.07 to 0.37, p=0.006). In the same adjusted model, a similar effect modification was observed between healthcare system delay of ≤120 min or >120 min and RIC+pPCI on MSI, although with borderline significance (p=0.08).
Discussion
The main finding of the present study is that RIC attenuated the detrimental effect of healthcare system delay on myocardial salvage in patients with STEMI undergoing pPCI. While healthcare system delay was negatively associated with MSI in patients treated with pPCI alone, this association was not present in patients treated with RIC+pPCI. The cardioprotective effect of RIC increased with extended healthcare system delay. As statistical power was limited, the present study should be considered explorative.
In our study, the beneficial effect of RIC was shown by an increase in MSI, which represents the fraction of the ischaemic threatened myocardium salvaged by reperfusion treatment. In patients suffering from acute myocardial infarction, 99Tc-sestamibi-assessed MSI has been shown to be a predictor of mortality.20 Thus, the findings of the present study may have clinical implications.
Although healthcare system delay is a well-known determinant of myocardial salvage, infarct size, left ventricle function6 and clinical outcome7 ,8 in patients with STEMI, many healthcare systems are challenged by long delays due to insufficient prehospital diagnostics and field triage, long distances to pPCI centres and extended door-to-balloon times. Our findings suggest that RIC is a potential adjunct to reperfusion therapy in particular for patients with prolonged treatment delays as it may alleviate the detrimental effect of the healthcare system delay as well as treatment delay. We predominantly found cardioprotective effect of RIC in patients with healthcare system delay >120 min. However, RIC may be effective in patients with healthcare system delay ≤120 min although to a lower extent and not statistically significant in the present study. The latter could be a result of small sample size, insufficient statistical power and inclusion of patients with very short healthcare system delay and minor potential for a cardioprotective effect of RIC due to a slight ischaemic injury. Importantly, application of RIC in patients with healthcare system delay >120 min increased myocardial salvage to a similar extent as in patients with healthcare system delay ≤120 min, suggesting that RIC may prolong the window for pPCI as the preferred reperfusion strategy. In our study, ambulance personnel performed the RIC procedure with a standard blood pressure cuff, making it an easily applicable, low-cost strategy. Notably, as demonstrated in the present study, administration of RIC did not increase healthcare system delay. As recently demonstrated in studies by White et al11 and Prunier et al,12 the prehospital timing of RIC administration is not a requisite for achievement of a cardioprotective effect in patients with STEMI. Application of RIC may be effective even when initiated at the time of pPCO centre arrival.
The mechanism underlying RIC is not completely understood. RIC is an innate adaptive mechanism promoting tolerance to ischaemia–reperfusion injury in multiple organs through a complex cascade of events involving triggers, neuronal and humoral signalling pathways and target organ effectors.9 As healthcare system delay reflects on-going ischaemia in patients with STEMI prior to reperfusion therapy, our findings indicate that the cardioprotective effect of RIC against myocardial cellular ischaemia–reperfusion injury increases with the duration of ischaemia. This finding is in accordance with experimental observations of local ischaemic preconditioning,21 ,22 while studies of ischaemic postconditioning are more ambiguous.23 ,24 However, with very long ischaemia duration, cardioprotection from ischaemic conditioning seems to be lost.22 ,25
In addition to RIC, the antithrombotic medications used for treating patients with STEMI may itself have infarct sparring effects, that is, P2Y12 receptor antagonists and glycoprotein IIb/IIIa inhibitors.26 Analogues to our findings may be drawn to the experience with use of the glycoprotein IIb/IIIa inhibitor tirofiban for patients with STEMI, for which pretreatment with tirofiban may confer cardioprotective effects27 and improve clinical outcome.28 Notably, a post-hoc subanalysis demonstrated that the highest efficacy of tirofiban treatment was seen in patients with long healthcare system delays and tirofiban pretreatment time.29 A recent Danish register-based study demonstrated that a healthcare system delay of ≤120 min was achieved for >80% of patients with STEMI.30 Despite a markedly improvement in healthcare system performance, this indicates that there is still a significant number of patients with STEMI challenged by prolonged healthcare system delays and for whom in particular there is a need for adjunctive therapy strategies. Although, our findings need to be consolidated, they suggest that RIC may be a potential adjunctive treatment strategy for patients with STEMI especially those challenged by long healthcare system delays.
Limitations
The present study is a post-hoc analysis of a randomised controlled trial. The power calculation of the parent trial was based on MSI as primary end point but was not powered for subgroup analysis. As a consequence, this study should be considered exploratory. In the parent trial, a number of patients were excluded following randomisation or did not obtain data for MSI. However, no indication of selection bias was found when assessed in the parent trial.10
Treatment delay for reperfusion therapy in patients with STEMI, that is, symptom onset to reperfusion therapy, is determined by both patient delay, being the time from symptom onset to first medical contact, and healthcare system delay, being the time from first medical contact to reperfusion therapy. Treatment delay represents the true extent of total ischaemia duration. However, patient delay cannot be accurately determined and acknowledgement of the specific STEMI onset is difficult and might be hampered by both recall bias and misinterpretation of symptoms not deriving from or preceding the actually time of STEMI. In contrast, healthcare system delay is objective and less variable for comparison use than treatment delay. While healthcare system delay is independently associated with mortality in patients with STEMI, a similar association for treatment delay remains controversial. Consequently, we chose to focus primarily on healthcare system delay in the present study. Nevertheless, the findings of the present study need to be further exploited, and a causal relation between the cardioprotective effects of RIC and the detrimental effects of delay to reperfusion therapy should be sought.
Conclusion
RIC as an adjunctive to pPCI attenuated the detrimental effect of healthcare system delay on myocardial salvage in patients with STEMI. Our findings suggest that the cardioprotective effect of RIC increases with the duration of ischaemia.
Key messages
What is already known on this subject?
Healthcare system delay is inevitable in treating patients with ST-segment elevation myocardial infarction and is negatively associated with clinical outcome.
What might this study add?
Remote ischaemic conditioning as an adjunctive to primary percutaneous coronary intervention (pPCI) attenuated the detrimental effect of healthcare system delay on myocardial salvage in patients with ST-segment elevation myocardial infarction.
The cardioprotective effect of remote ischaemic conditioning increased with extended healthcare system delay.
How might this impact on clinical practice?
Remote ischaemic conditioning is a promising adjunctive therapy for patients with ST-segment elevation myocardial infarction undergoing pPCI and may prolong the window for pPCI as the preferred reperfusion strategy.
Acknowledgments
We thank Ingunn Skogstad Riddervold from the Research Department, Prehospital Emergency Medical Services, Central Denmark Region for invaluable assistance in regard to data collection and verification.
References
Footnotes
Collaborators CONDI Investigators: M Bøttcher, AK Kaltoft, NH Andersen, TM Hansen, S Trautner, JF Lassen, EH Christiansen, LR Krusell, SD Kristensen, L Thuesen, M Rehling and TT Nielsen.
Contributors KP, MRS and HEB did the data analysis and drafting of the manuscript. All authors participated in data acquisition and critical revision of the manuscript.
Funding The Danish Council for Independent Research (11-108354), Fondation Leducq (06CVD).
Competing interests MRS and HEB are shareholders in CellAegis Devices.
Ethics approval The Danish Committee on Health Research Ethics, The Danish Data Protection Agency.
Provenance and peer review Not commissioned; externally peer reviewed.