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The Impact of Out-of-Hours Presentation on Clinical Outcomes in ST-Elevation Myocardial Infarction
HLC 2942 No. of Pages 10
Heart, Lung and Circulation (2019) xx, 1–10 1443-9506/04/$36.00 https://doi.org/10.1016/j.hlc.2019.05.184
ORIGINAL ARTICLE
The Impact of Out-of-Hours Presentation on Clinical Outcomes in ST-Elevation Myocardial Infarction Sinjini Biswas, MBBS a,b,1, Angela Brennan, RN a,1, Stephen J. Duffy, MBBS, PhD a,b, Nick Andrianopoulos, MBBS, MBiostat a, William Chan, MBBS, PhD b,c,k, Antony Walton, MBBS b, Samer Noaman, MBChB b, James A. Shaw, MBBS, PhD b, Andrew Ajani, MBBS, MD a,c,d, David J. Clark, MBBS, DMedSci e, Melanie Freeman, MBBS f, Chin Hiew, MBBS g, Ernesto Oqueli, MD h,i, Jeffrey Lefkovits, MBBS a,d, Christopher M. Reid, PhD a,j, Dion Stub, MBBS, PhD a,b,k* a
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia Department of Cardiology, The Alfred Hospital, Melbourne, Vic, Australia c Department of Medicine, University of Melbourne, Melbourne, Vic, Australia d Department of Cardiology, Royal Melbourne Hospital, Melbourne, Vic, Australia e Department of Cardiology, Austin Health, Melbourne, Vic, Australia f Department of Cardiology, Box Hill Hospital, Melbourne, Vic, Australia g Department of Cardiology, University Hospital Geelong, Geelong, Vic, Australia h Department of Cardiology, Ballarat Health Services, Ballarat, Vic, Australia i School of Medicine, Deakin University, Ballarat, Vic, Australia j School of Public Health, Curtin University, Perth, WA, Australia k Baker IDI Heart and Diabetes Institute, Melbourne, Vic, Australia b
Received 13 July 2018; received in revised form 26 March 2019; accepted 1 May 2019; online published-ahead-of-print xxx
Background
Systems of care have been established to ensure patients with ST-elevation myocardial infarction (STEMI) get timely access to primary percutaneous coronary intervention (PPCI). In this study, we evaluated whether patients undergoing PPCI both in-hours and out-of-hours experience similar care and clinical outcomes.
Methods
Of 9,865 patients who underwent PCI for STEMI from 2005 to 2016 and were enrolled in the multi-centre Melbourne Interventional Group registry, patients who had initially presented to a non-PCI capable hospital, received thrombolysis or presented >12 hours post-symptom onset were excluded. Our final study cohort of 4,590 patients were dichotomised by whether PPCI was performed in-hours or out-of-hours, and compared. The primary outcome was 30-day mortality.
Results
The in-hours group included 1,865 patients (40.6%) while 2,725 patients (59.4%) had out-of-hours PPCI. Patients presenting out-of-hours had longer median door-to-balloon time (DTBT; 83 [IQR 61–109] vs. 60 [IQR 41–88] mins, p < 0.01) and were more likely to receive a drug-eluting stent (p = 0.001). Procedural
*Corresponding author at: Department of Cardiology, The Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia. Tel.: +61 3 9076 3263; Fax: +61 3 9076 2461, Email: [email protected] 1
Co-primary authors on manuscript.
© 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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characteristics were otherwise similar although rates of radial access were low overall (18.4%). No differences in in-hospital, 30-day or 12-month mortality were observed between the groups (p = NS). On Cox proportional hazards modelling, out-of-hours presentation was not an independent predictor of 30-day mortality (HR 0.94, 95% CI 0.71–1.22). A landmark analysis of data from 2012 did not change the primary outcome.
Conclusion
Despite a slightly longer DTBT, patients undergoing PPCI out-of-hours experienced similar care and clinical outcomes to the in-hours group. Given the majority of patients with STEMI present out-of-hours, these data have implications for STEMI systems of care.
Keywords
ST-elevation myocardial infarction Primary percutaneous coronary intervention Outcomes Outof-hours presentation
Introduction In the last two decades, reperfusion of patients with STelevation myocardial infarction (STEMI) with urgent or primary percutaneous coronary intervention (PPCI) has become a mainstay of acute cardiac management. The importance of timely access to reperfusion with PPCI has been increasingly recognised with several analyses showing worsening survival in STEMI patients with longer door-to-balloon times [1,2]. As a result, robust systems of care have been developed in PCI-capable centres to allow for rapid mobilisation of oncall teams so that timely reperfusion can occur even when the patient presents outside of normal working hours. Some single-centre studies have demonstrated worse outcomes in patients undergoing PPCI outside of normal working hours compared to those treated in-hours [3]. This trend was also observed for cardiac patients admitted after-hours in general [4]. More recently, however, a subgroup analysis of the Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention (CHAMPION PHOENIX) study data showed no difference in in-hospital or 30-day major adverse cardiovascular events (MACE), which may reflect contemporary improvements in STEMI care [5]. Knowing whether differences exist in procedural factors and outcomes between in-hours and out-of-hours PPCI is crucial to improving the care of patients with STEMI. We therefore sought to determine whether there were any differences in reperfusion time, procedural characteristics or clinical outcomes between in- versus out-of-hours PPCI patients in a multi-centre Australian PCI registry.
Methods This was a retrospective cohort study of consecutive patients undergoing PPCI for STEMI from 1 January 2005 to 31 December 2016 inclusive, enrolled prospectively in the Melbourne Interventional Group (MIG) registry. PPCI was defined as urgent PCI in patients with STEMI who are within 12 hours of symptom onset. Patients who had PCI post thrombolysis and those who had inter-hospital transfer to a PCI-capable hospital were excluded. The MIG registry is a multi-centre PCI registry and has
previously been described in detail [6]. Briefly, demographic, clinical, procedural and in-hospital outcome data are prospectively recorded on case-report forms using standardised definitions for all fields with telephone follow-up and medical record review performed at 30 days and 12 months [7]. There are four participating hospitals located in metropolitan Melbourne and two hospitals in major regional cities in Victoria, that all have 24-hour cardiac catheterisation laboratory services. An audit of a number of verifiable fields from 5% of randomly selected procedures at each institution is undertaken periodically [8]. In the most recent audit, 27 fields were assessed with data accuracy of 98%. This compares favourably to audits from other large registries [9]. The primary ethics approval has been granted by the ethics committee at The Alfred Hospital (approval number 92/04), and also approved by each participating hospital, including the use of ‘‘opt-out” consent as previously described [7]. Patients were divided into two groups according to time of PPCI. Out-of-hours PPCI was defined by intervention performed during weekdays from 6 pm to 8 am and at any time during weekends and public holidays. In-hours PPCI was defined as procedures performed between 8 am to 6 pm on weekdays (excluding public holidays). Baseline and procedural characteristics, as well as short- and long-term clinical outcomes were compared between the two groups (definitions shown in Supplementary Table 1). The primary endpoint was 30-day mortality. Secondary endpoints included MACE and complications such as bleeding, stroke and target vessel revascularisation (TVR) during the index admission, and at 30-day and 12-month follow-up, in-hospital and 12month mortality, as well as door-to-balloon time (DTBT). MACE was defined as a composite of all-cause mortality, myocardial infarction and TVR. Only bleeding events that prolonged hospital stay and/or required a transfusion and/ or caused a fall in haemoglobin by >3.0 g/dL, were included. A landmark analysis of data from 2012 onwards was also performed to evaluate outcomes in a more contemporary study cohort. Continuous variables are expressed as mean standard deviation, and categorical data are expressed as numbers and percentages. Continuous variables were compared using the independent t-test or Mann-Whitney U test. Categorical variables were compared using Fisher’s exact test or Chi-square
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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test as appropriate. The Kaplan-Meier method was used to estimate event-free survival rates and the log-rank test was used for survival comparisons. To determine whether out-ofhours PPCI was an independent predictor of 30-day mortality, in addition to out-of-hours PPCI, 28 other clinically relevant variables including gender, cardiovascular risk factors like diabetes mellitus and hypertension, history of previous MI, disease extent on angiography and lesion location for PPCI, were considered. Aside from the timing of PPCI variable which was forced into the model (HR 0.91, 95% CI 0.75–1.10, p = 0.33 on univariate analysis), only variables with a p value of <0.1 on univariate analysis that were not co-linear were entered into a stepwise backward selection modelling process for multivariable assessment. Cox proportional hazards modelling (log likelihood = -1,569.5) was used in this study. While the model failed the proportional hazards assumption when the timing of PPCI variable (out-ofhours vs. in-hours) was forced into the model (global test p = 0.003), the proportional hazards assumption was satisfied when this variable was excluded (global test p = 0.107). Given this finding as well as the similarities seen in the results of a multivariable logistics regression model and the Cox proportional hazards model, further modelling was not performed as it would be unlikely for such models to show a significant association between out-of-hours PPCI and 30-day mortality hazard. Complete case analysis was performed for purposes of multivariable modelling (i.e. patients with missing values were excluded). All statistical analyses were performed using Stata 13.1 software (StataCorp LP, College Station, TX, USA). A twosided p value of <0.05 was considered statistically significant.
Results In total, 9,865 patients underwent PCI for STEMI at the participating hospitals in the registry. Of these patients, 1,133 patients had received thrombolysis prior to PCI, 2,092 patients had initially presented to a non-PCI capable hospital, and 2,050 patients had presented with symptom onset >12 hours prior and did not meet our definition of PPCI, and therefore were excluded (Figure 1). Consequently, the study cohort included 4,590 patients who underwent PPCI for STEMI during the study period and met our inclusion criteria. Of these, 1,865 patients (40.6%) were treated inhours and 2,725 patients (59.4%) were treated out-of-hours. Overall, the mean age was 63.1 12.7 years and 3,637 patients (79.2%) were male. Table 1 shows the baseline demographics and clinical presentation of the two groups. Patients in the out-of-hours group were younger (62.1 12.6 years vs. 64.6 12.6 years, p < 0.001). The two groups were otherwise very similar in baseline demographics, cardiovascular risk factors and presentation characteristics. There were also no major differences in procedural characteristics such as access route, lesion complexity and proportion of unsuccessful PCI procedures, between the two groups (all p > 0.05) (Table 2). However, drug-eluting stent (DES) use was higher in the out-of-hours PPCI group (43.5% vs. 38.5%, p < 0.001). In terms of times to presentation, median symptom-todoor time (STDT) was slightly shorter in the out-of-hours group compared to the in-hours group (95 [IQR 65–148] mins vs. 100 [IQR 67–155] mins, p = 0.04) (Table 1). However, the proportion of cases in which pre-hospital notification was received was significantly lower in the out-of-hours group
Figure 1 Consort Diagram for Cohort Selection. Abbreviations: PCI, percutaneous coronary intervention; MIG, Melbourne Interventional Group; STEMI, ST-elevation myocardial infarction.
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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Table 1 Baseline Demographic & Clinical Characteristics. PPCI in-hours
PPCI out-of-hours
P-value
1,865 64.6 12.6
2,725 62.1 12.6
– <0.001
1,458 (78.2%)
2,179 (80.0%)
0.14
27.5 4.9
28.1 5.1
0.98
307 (16.5%)
450 (16.5%)
0.96
Hypertension
1,015 (54.5%)
1,395 (51.3%)
0.03
Dyslipidaemia
893 (48.1%)
1,311 (48.2%)
0.94
Current/previous smoker
1,172 (64.3%)
1,736 (65.2%)
0.53
Estimated glomerular filtration rate > 60 ml/min/1.73m2 Estimated glomerular filtration rate 30 – 60 ml/min/1.73m2
1,178 (74.7%) 359 (22.8%)
1,809 (72.8%) 621 (25.0%)
0.22
Number of patients Mean age SD (years) Male Mean body mass index SD (kg/m2) Diabetes mellitus
Estimated glomerular filtration rate < 30 ml/min/1.73m
2
41 (2.6%)
55 (2.2%)
Previous myocardial infarction
235 (12.6%)
340 (12.5%)
0.92
Family history of coronary artery disease
556 (31.2%)
926 (35.8%)
0.002
Previous heart failure (>2 weeks prior)
30 (1.6%)
40 (1.5%)
0.70
Previous stroke
86 (4.6%)
119 (4.4%)
0.69
Peripheral vascular disease
53 (2.9%)
86 (3.2%)
0.54
149 (8.0%) 213 (11.4%)
233 (8.6%) 290 (10.7%)
0.50 0.40
Chronic obstructive pulmonary disease Prior percutaneous coronary intervention Prior coronary artery bypass graft surgery
43 (2.3%)
56 (2.1%)
0.56
Post out-of-hospital cardiac arrest
218 (11.7%)
320 (11.7%)
0.96
Cardiogenic shock
214 (11.5%)
296 (10.9%)
0.52
95 [IQR 65–148]
100 [67–155]
0.04
60 [41–88]
83 [61–109]
<0.001
168 [128–239]
188 [147–248]
<0.001
1,440 (77.5) 524 (55.5)
1,581 (58.3) 718 (48.1)
<0.001 <0.001
Symptom-to-door time (minutes), median [IQR] Door-to-balloon time (minutes), median [IQR] Symptom-to-balloon time (minutes), median [IQR] Door-to-balloon time <90 minutes Pre-hospital notification received Abbreviation: PPCI, primary percutaneous coronary intervention.
(48.1% vs. 55.5%; p < 0.001) and median DTBT was significantly longer in the out-of-hours group compared to the inhours group (83 [IQR 61–109] mins vs. 60 [IQR 41–88] mins; p < 0.001). In addition, the proportion of patients achieving the target DTBT less than 90 minutes was also significantly lower in the out-of-hours group (58.3% vs. 77.5%, p < 0.001). Consequently, median total ischaemic time (i.e. STBT) was longer in those undergoing PPCI out-of-hours, compared to inhours (188 [IQR 147–248] mins vs. 168 [128–239] mins, p < 0.001). Similar differences in STDT, DTBT and STBT were seen by time of presentation in both metropolitan and regional hospitals in our registry (Supplementary Table 2). Over the 12-year study period, DTBT for both the groups has steadily fallen over the period (both p for trend <0.001) (Supplementary Figure 1). In contrast, median STDT has remained relatively stable in the in-hours group, while it has increased over time in the out-of-hours group (p for trend <0.001) (Supplementary Figure 2). Table 3 shows a comparison of in-hospital, 30-day and 12month outcomes between the two groups. A total of 323 patients (7.0%) in the study died during the index hospital admission. There was no significant difference in in-hospital
mortality or MACE between the two groups (6.8% vs. 7.4%, p = 0.50 and 9.6% vs. 9.8%, p = 0.87 respectively). There were also no significant differences in 30-day and 12-month mortality or MACE between the two groups. In addition, no significant difference in use of dual antiplatelet therapy (DAPT) was seen at 30 days post-PCI, although there was a trend towards lower use of DAPT in the in-hours cohort at 12 months. Overall, there was no change in 30-day mortality or MACE rates over the study period (p for trend = 0.19 and 0.14 respectively [Supplementary Table 3]). The rates of other complications such as major bleeding, peri-procedural myocardial infarction and target vessel revascularisation were similar in both groups during the index hospital admission, as well as at 30-day and 12-month follow-up (all p > 0.05). The 30-day and 12-month readmission rates were also similar between the two groups (both p > 0.05). Similar results were seen regardless of whether the patient was treated at a metropolitan or regional hospital, with no differences in in-hospital, 30-day or 12-month outcomes (all p > 0.05) (Supplementary Table 2). In a Cox proportional hazards model, the three strongest independent predictors of 30-day mortality were found to be
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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Table 2 Angiographic and Procedural Characteristics. PPCI in-hours
PPCI out-of-hours
P-value
1,865 327 (17.5%)
2,725 518 (19.0%)
0.23
1,536 (82.4%)
2,200 (80.7%)
Single vessel disease
870 (46.7%)
1,253 (46.0%)
Multi-vessel disease
995 (53.4%)
1,470 (54.0%)
Number of patients Radial access Femoral access
-
Extent of coronary disease: 0.67
Ostial lesion
149 (6.9%)
242 (7.7%)
0.28
Bifurcation lesion
237 (10.9%)
358 (11.3%)
0.65
1,568 (72.3%) 13 (0.6%)
2,239 (70.9%) 31 (1.0%)
0.26 0.13
30 (1.6%)
48 (1.8%)
0.69
AHA/ACC Type B2/C lesion Left main percutaneous coronary intervention Multi-vessel percutaneous coronary intervention TIMI flow grade pre- percutaneous coronary intervention TIMI 0 flow
1,442 (66.7%)
2,040 (64.7%)
TIMI 1 flow
99 (4.6%)
188 (6.0%)
TIMI 2 flow
238 (11.0%)
305 (9.7%)
TIMI 3 flow
0.02
384 (17.8%)
620 (19.7%)
TIMI 3 flow post- percutaneous coronary intervention Thrombectomy device
2,016 (93.0%) 522 (27.2%)
2,954 (93.6%) 731 (25.5%)
0.44 0.19
Glycoprotein IIb/IIIa inhibitor
0.70
1,270 (68.1%)
1,869 (68.6%)
Intra-aortic balloon pump
122 (9.2%)
184 (10.0%)
0.46
Drug-eluting stent
717 (38.5%)
1,186 (43.5%)
0.001
Acute complications: Acute closure
24 (1.1%)
18 (0.6%)
0.03
Dissection
99 (4.6%)
93 (2.9%)
0.002
Perforation Transient/persistent no-reflow
5 (0.2%) 140 (6.5%)
11 (0.4%) 158 (5.0%)
0.44 0.02
Unsuccessful percutaneous coronary intervention
97 (4.5%)
130 (4.1%)
0.52
1,126 (64.9%)
1,607 (62.8%)
570 (32.9%)
886 (34.6%)
39 (2.3%)
67 (2.6%)
Left ventricular ejection fraction: Left ventricular ejection fraction >45% Left ventricular ejection fraction 30–45% Left ventricular ejection fraction <30%
0.33
Abbreviation: PPCI, primary percutaneous coronary intervention.
presentation with cardiogenic shock (HR 4.49, 95% CI 3.25– 6.19, p < 0.001), severe left ventricular systolic dysfunction defined as a left ventricular ejection fraction (LVEF) <30% (HR 4.06, 95% CI 2.66–6.20, p < 0.001) and stage 4–5 chronic kidney disease (HR 3.97, 95% CI 2.49–6.34, p < 0.001) (Table 4). Out-of-hours PPCI was not found to be an independent predictor of 30-day mortality (HR 0.94, 95% CI 0.71–1.22, p = 0.63). Kaplan-Meier survival curves are shown in Figure 2 and Supplementary Figure 3. These demonstrated that while 30-day survival was worse in the in-hours group (log-rank p = 0.02) there was no difference in long-term survival between the outof-hours and in-hours PPCI groups (log-rank p = 0.43). When patients with cardiogenic shock and presentation post-OHCA were excluded, the three strongest predictors of 30-day mortality in a Cox proportional hazards model were found to be severe left ventricular systolic dysfunction defined as LVEF < 30% (HR 11.32, 95% CI 7.51–17.06, p < 0.001), stage 4–5 chronic kidney disease (HR 7.51, 95% CI
4.81–11.74, p < 0.001) and stage 3 chronic kidney disease (HR 3.30, 95% CI 2.44–4.47, p < 0.001) (Supplementary Table 4). A DTBT<90 minutes was found to be an independent protective factor (HR 0.71, 95% CI 0.54–0.93, p = 0.01). Out-of-hours PPCI was again not found to be an independent predictor of 30-day mortality (HR 0.80, 95% CI 0.61–1.05, p = 0.11). In a landmark analysis of data from 2012 onwards, median door-to-balloon time continued to be significantly longer in the out-of-hours PPCI group (74 [IQR 55–99] mins vs. 51 [IQR 37– 76] minutes, p < 0.001) and the proportion of patients achieving a DTBT<90 minutes in the out-of-hours PPCI group was also lower (67.2% vs. 83.1%, p < 0.001) (Supplementary Table 5). Drug eluting stent (DES) use was higher and importantly equivalent in the out-of-hours and in-hours PPCI groups (55.1% vs. 52.4%, p = 0.30) (Supplementary Table 6). However, in-hospital, 30-day and 12-month outcomes were again similar between the in-hours and out-of-hours PPCI groups (Supplementary Table 7) (all p > 0.05). In a Cox proportional hazards
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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Table 3 In-Hospital, 30-Day and 12-Month Outcomes. PPCI in-hours
PPCI out-of-hours
P-value
IN-HOSPITAL Death
137 (7.4%)
186 (6.8%)
0.50
Peri-procedural myocardial infarction
22 (1.2%)
39 (1.4%)
0.47
Target vessel revascularisation
44 (2.4%)
75 (2.8%)
0.41
Major adverse cardiovascular events
182 (9.8%)
262 (9.6%)
0.87
Major bleeding
83 (4.5%)
116 (4.3%)
0.75
15 (0.9)
19 (0.8)
0.63
150 (8.0%) 34 (1.8%)
201 (7.4%) 55 (2.0%)
0.40 0.64
Stent thrombosis 30-DAY Death Myocardial infarction Target vessel revascularisation
54 (2.9%)
100 (3.7%)
0.15
Major adverse cardiovascular events
213 (11.4%)
306 (11.2%)
0.84
Readmission
226 (13.2%)
367 (14.6%)
0.21
16 (1.0)
19 (0.8)
0.64
1,537 (93.8)
2,285 (93.8)
0.97
183 (11.9%) 68 (4.4%)
241 (11.1%) 92 (4.2%)
0.45 0.78
Stent thrombosis Use of dual antiplatelet therapy 12-MONTH Death Myocardial infarction Target vessel revascularisation
119 (7.7%)
182 (8.4%)
0.48
Major adverse cardiovascular events
324 (21.0%)
436 (20.0%)
0.46
Readmission
470 (34.7%)
692 (35.8%)
0.42
834 (66.7)
1,244 (70.1)
0.05
Use of dual antiplatelet therapy Abbreviation: PPCI, primary percutaneous coronary intervention.
Table 4 Independent Predictors of 30-Day Mortality. Hazard ratio
95% Confidence Interval
P-value
Left ventricular ejection fraction Left ventricular ejection fraction >45%
1 (ref)
Left ventricular ejection fraction 30–45%
2.14
1.57–2.92
<0.001
Left ventricular ejection fraction <30%
4.06
2.66–6.20
<0.001
Estimated glomerular filtration rate (eGFR) eGFR >60 ml/min/1.73m2
1 (ref)
eGFR 30–60 ml/min/1.73m2
2.10
1.56–2.83
<0.001
eGFR <30 ml/min/1.73m2
3.97
2.49–6.34
<0.001
Out-of-hospital cardiac arrest
3.85
2.84–5.22
<0.001
Cardiogenic shock
4.49
3.25–6.19
<0.001
Chronic lung disease
1.58
1.09–2.30
0.02
Hypertension
1.60
1.19–2.15
0.002
Age (per year increase) Time of primary percutaneous coronary intervention (PPCI)
1.03
1.02–1.04
<0.001
In-hours PPCI
1 (ref)
Out of hours PPCI
0.94
0.71–1.22
0.63
Drug-eluting stent use
0.68
0.50–0.91
0.01
PPCI to right coronary artery lesion
0.47
0.34–0.65
<0.001
Abbreviations: eGFR, estimated glomerular filtration rate; PPCI, primary percutaneous coronary intervention.
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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Figure 2 Kaplan-Meier curves of short-term survival for patients undergoing in-hours vs. out-of-hours primary PCI for STEMI. Abbreviations: PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
model, out-of-hours PPCI was not found to be an independent predictor of 30-day mortality in this more contemporary cohort of patients (Supplementary Table 8).
Discussion This large, multi-centre study of consecutive patients with STEMI undergoing PPCI showed that patients undergoing PPCI out-of-hours had a longer median DTBT while fewer patients achieved the target DTBT of less than 90 minutes when PPCI was performed out-of-hours. However, the magnitude of the delay in reperfusion in patients undergoing outof-hours PPCI had no significant impact on key clinical outcomes including in-hospital and 30-day mortality. Even when patients with cardiogenic shock and those post outof-hospital-cardiac-arrest (OHCA) at presentation were excluded, out-of-hours PPCI was not independently associated with 30-day mortality. Over the study period, while median DTBT for both in-hours and out-of-hours PPCI has significantly fallen, the difference in times between the two groups has not changed significantly. Consequently, total ischaemic time has remained longer in the out-of-hours group compared to in-hours. Despite improvements in PCI practice including stent technology and antiplatelet therapy over the study period, there has been no overall change in 30-day mortality, both for in-hours and out-of-hours PPCI. Overall, patients undergoing PPCI receive similar care regardless of time of presentation. There are many reasons why the outcomes of PPCI may differ in patients presenting outside normal working hours including potential differences in patients’ baseline characteristics or procedural factors such as the use of adjunctive
therapies and rates of complications. A circadian variation in the efficacy of fibrinolytic therapy to re-establish flow in coronary arteries with acute thrombotic occlusion has been described, most likely due to alterations in the balance between prothrombotic factors and intrinsic fibrinolytic factor at different times of day [10]. In particular, levels of natural fibrinolytic factors have been shown to be higher in the evening hours while platelet aggregation is increased in the early morning hours [11,12]. While these findings are mostly based on studies performed in patients treated with thrombolysis, they may still be relevant in a PPCI cohort like ours with respect to the how easily antegrade flow can be restored in the infarct-related artery out-of-hours. Apart from patients in the out-of-hours group being slightly younger, the two groups in our study were quite well-matched in terms of baseline and procedural characteristics. In contrast to some other studies, the proportions of high-risk STEMI patients presenting with cardiogenic shock or post-OHCA were also similar between the two groups, as was the extent of disease and lesion complexity found on angiography [13]. However, the proportion of patients with cardiogenic shock undergoing PCI in our study overall was high when compared to other PCI registries (e.g. <3% in the Swedish Coronary Angiography and Angioplasty Registry in 2012 vs. 10.0% in the MIG registry in 2012), which may explain our relatively high rates of 12-month mortality and MACE [14]. Drug eluting stent use was higher in the out-of-hours group, although the absolute magnitude of difference was small and potentially related to operator preference at hospitals that perform more out-of-hours PPCI. DES use has also increased over time and in patients treated from 2012 onwards, DES use was similar between the two groups. Of note, DES use was found to be protective on multivariable analysis while increased age and
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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history of hypertension were independent risk factors. The higher DES use in the out-of-hours group along with these patients being younger and less likely to have hypertension may explain to an extent why outcomes in the out-of-hours group were not inferior to the in-hours group. Overall, the proportion of patients having an unsuccessful PCI or post-PCI TIMI flow <3 were similar in both groups. This suggests no deterioration in the quality of PPCI when it was performed outof-hours, which could be expected as a result of factors such as operator fatigue [13]. The significant differences in reperfusion times between inhours and out-of-hours PPCI seen in our study is similar to previous reports [15,16,17,18,19]. While median DTBT has fallen over the study period in both groups, overall it was still 23 minutes longer in the out-of-hours group compared to the inhours group. Despite this treatment delay, our study showed no difference in in-hospital or intermediate-term mortality between the in-hours and out-of-hours PPCI groups. Previous studies have shown that a 30-minute delay in DTBT is associated with a 20–30% relative increase in in-hospital mortality regardless of baseline DTBT [1,2,20]. This suggests that, given the significant improvements in DTBT that have already been made by incorporating strategies such as pre-hospital ambulance notification of STEMI and streamlined STEMI on-call teams, as well as improved stent technology and adjunctive pharmacotherapy, there may be little clinical benefit from trying to reduce the small inherent delay in out-of-hours cases any further with more expensive and resource-intensive measures such as having on-call STEMI teams stay on site outside of working hours, as is used in certain hospital systems [21,22,23]. Many previous studies, which have shown a mortality hazard in patients with acute myocardial infarction admitted on weekends or out-of-hours, have, in general included a heterogeneous patient population, including those treated with thrombolysis [24,25,26,27,28]. In contrast, studies that have included patients with STEMI treated by PPCI only, including a recent meta-analysis of 86,776 patients from 39 studies, have shown similar results to ours with no difference in both inhospital and longer-term mortality regardless of timing of PPCI [29,30,31,32,33,34,35,36]. Our study also showed no differences in rates of recurrent MI or target vessel revascularisation between the two groups. While there was also no difference in in-hospital bleeding between the two groups, we did, however, note that rates of bleeding complications in our study were higher overall when compared to similar contemporary studies [29]. This may be due to the higher proportion of femoral access cases in our cohort, as well as the use of different definitions of bleeding. Indeed, our analysis of data from 2012 onwards demonstrated a higher proportion of radial access cases as well as a slight drop in rates of bleeding complications, a trend which we expect to see continue. In our study, we noted that median STDT was shorter by 5 minutes in the out-of-hours group compared to the in-hours group. This has also been reported in other studies, and may have occurred as patients with cardiac symptoms may initially present to other health care services that are available during working hours such as their primary care physician,
rather than presenting directly to an emergency department or calling an ambulance, leading to delays in STDT [37,38]. We also noted that patients presenting out-of-hours were more likely to have pre-hospital notification by ambulance services, which may have an impact on STDT. Unfortunately, there was no significant improvement in STDT over the study period, and of particular concern was the increasing median STDT seen in the out-of-hours group over time in our study (Supplementary Figure 2). Overall, only 20.7% of patients in our study presented within the first hour of onset of symptoms, regardless of time of procedure, indicating that increased focus needs to be placed in improving community awareness of early warning signs of myocardial infarction (MI) and the appropriate action plan. Media campaigns have been shown to have an impact on reducing delays to presentation and could be utilised further in the future [39]. Our study had a number of limitations. This was a retrospective analysis of patients enrolled prospectively in a PCI registry, which brings its own inherent limitations including an inability to account for all confounders. Secondly, our study may not have been powered to detect a difference in survival given the small difference in DTBT between the groups. Other studies have shown that such a difference in DTBT may result in more long-term left ventricular dysfunction and heart failure readmissions, but not be enough to cause mortality hazard [40,41]. Our study did not evaluate for differences in infarct size or long-term left ventricular dysfunction between out-of-hours and in-hours PPCI, which would be important to assess in future work. Thirdly, our study had a long inclusion period, during which time, PPCI practice has evolved. Therefore, to an extent, our study reflects outcomes in a historical cohort of patients. However, outcomes after PPCI have remained unchanged over this study period suggesting that our results are still applicable to contemporary PPCI patients. In addition, a landmark analysis of data from 2012 onwards did not show any significant difference in results. Finally, we only included patients undergoing PPCI; therefore, these results may not be generalisable to patients with STEMI who receive medical management only or undergo PCI post-thrombolysis. In conclusion, this large, multi-centre observational realworld study demonstrates that, despite a small increase in door to balloon time, there is no difference in mortality or MACE following PPCI whether it is performed in-hours or out-of-hours. Our findings reassuringly demonstrate consistent procedural and clinical quality across multiple PPCI centres regardless of time of presentation. While hospitals should continue to improve processes to minimise delays to PPCI, the small inherent delays that occur for out-of-hours cases are not long enough to adversely affect outcomes in these patients.
Funding and Disclosures We would like to acknowledge the following sources of scholarship/grant support: The National Heart Foundation
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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of Australia (Dr Biswas: reference no. 101518; Dr Stub: reference no. 101908), the National Health and Medical Research Council of Australia (Professor Duffy: reference no. 1111170, Dr Chan: reference no. 1052960, Professor Reid: reference no. 1045862), the Australian Government Research Training Program (Dr Biswas) and the Viertel Foundation (Dr Stub). The Melbourne Interventional Group acknowledges funding from Abbott, Astra-Zeneca, Medtronic, MSD, Pfizer, Servier and The Medicines Company. These companies do not have access to data and do not have the right to review manuscripts or abstracts before publication.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.hlc. 2019.05.184.
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[14] Biswas S, Duffy SJ, Lefkovits J, Andrianopoulos N, Brennan A, Walton A, et al. Australian Trends in Procedural Characteristics and Outcomes in Patients Undergoing Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction. Am J Cardiol 2018;121(3):279–88. [15] Magid DJ, Wang Y, Herrin J, McNamara RL, Bradley EH, Curtis JP, et al. Relationship between time of day, day of week, timeliness of reperfusion, and in-hospital mortality for patients with acute ST-segment elevation myocardial infarction. JAMA 2005;294(7):803–12. [16] Kruth P, Zeymer U, Gitt A, Junger C, Wienbergen H, Niedermeier F, et al. Influence of presentation at the weekend on treatment and outcome in ST-elevation myocardial infarction in hospitals with catheterization laboratories. Clin Res Cardiol 2008;97(10):742–7. [17] Jneid H, Fonarow GC, Cannon CP, Palacios IF, Kilic T, Moukarbel GV, et al. Impact of time of presentation on the care and outcomes of acute myocardial infarction. Circulation 2008;117(19):2502–9. [18] Dasari TW, Roe MT, Chen AY, Peterson ED, Giugliano RP, Fonarow GC, et al. Impact of time of presentation on process performance and outcomes in ST-segment-elevation myocardial infarction: a report from the American Heart Association: Mission Lifeline program. Circ Cardiovasc Qual Outcomes 2014;7(5):656–63. [19] Graham MM, Ghali WA, Southern DA, Traboulsi M, Knudtson ML. Outcomes of after-hours versus regular working hours primary percutaneous coronary intervention for acute myocardial infarction. BMJ Qual Safety 2011;20(1):60. [20] Rathore SS, Curtis JP, Nallamothu BK, Wang Y, Foody JAM, Kosiborod M, et al. Association of Door-to-Balloon Time and Mortality in Patients 65 Years With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Am J Cardiol 2009;104(9):1198–203. [21] Bradley EH, Herrin J, Wang Y, Barton BA, Webster TR, Mattera JA, et al. Strategies for Reducing the Door-to-Balloon Time in Acute Myocardial Infarction. N Engl J Med 2006;355(22):2308–20. [22] Hutchison AW, Malaiapan Y, Jarvie I, Barger B, Watkins E, Braitberg G, et al. Prehospital 12-lead ECG to triage ST-elevation myocardial infarction and emergency department activation of the infarct team significantly improves door-to-balloon times: ambulance Victoria and MonashHEART Acute Myocardial Infarction (MonAMI) 12-lead ECG project. Circ Cardiovasc Interv 2009;2(6):528–34. [23] Allaqaband S, Jan MF, Banday WY, Schlemm A, Ahmed SH, Mori N, et al. Impact of 24-hr in-hospital interventional cardiology team on timeliness of reperfusion for ST-segment elevation myocardial infarction. Catheter Cardiovasc Interv 2010;75(7):1015–23. [24] Kostis WJ, Demissie K, Marcella SW, Shao YH, Wilson AC, Moreyra AE. Weekend versus weekday admission and mortality from myocardial infarction. N Engl J Med 2007;356(11):1099–109. [25] Sorita A, Ahmed A, Starr SR, Thompson KM, Reed DA, Prokop L, et al. Off-hour presentation and outcomes in patients with acute myocardial infarction: systematic review and meta-analysis. BMJ 2014;348:f7393. [26] Cubeddu RJ, Cruz-Gonzalez I, Kiernan TJ, Truong QA, Rosenfield K, Leinbach RC, et al. ST-elevation myocardial infarction mortality in a major academic center "on-" versus "off-" hours. J Invasive Cardiol 2009;21(10):518–23. [27] Maier B, Behrens S, Graf-Bothe C, Kuckuck H, Roehnisch JU, Schoeller RG, et al. Time of admission, quality of PCI care, and outcome of patients with ST-elevation myocardial infarction. Clin Res Cardiol 2010;99(9):565–72. [28] Hong JS, Kang HC, Lee SH. Comparison of case fatality rates for acute myocardial infarction in weekday vs weekend admissions in South Korea. Circ J 2010;74(3):496–502. [29] Rathod KS, Jones DA, Gallagher SM, Bromage DI, Whitbread M, Archbold AR, et al. Out-of-hours primary percutaneous coronary intervention for ST-elevation myocardial infarction is not associated with excess mortality: a study of 3347 patients treated in an integrated cardiac network. BMJ Open 2013;3(6). [30] Sadeghi HM, Grines CL, Chandra HR, Mehran R, Fahy M, Cox DA, et al. Magnitude and impact of treatment delays on weeknights and weekends in patients undergoing primary angioplasty for acute myocardial infarction (the CADILLAC trial). Am J Cardiol 2004;94(5). 637-40, a9. [31] Henriques JPS, Haasdijk AP, Zijlstra F. Outcome of primary angioplasty for acute myocardial infarction during routine duty hours versus during off-hours. J Am Coll Cardiol 2003;41(12):2138–42. [32] de Boer SPM, Oemrawsingh RM, Lenzen MJ, van Mieghem NM, Schultz C, Akkerhuis KM, et al. Primary PCI during off-hours is not related to increased mortality. Eur Heart J: Acute Cardiovasc Care 2012;1(1):33–9. [33] Casella G, Ottani F, Ortolani P, Guastaroba P, Santarelli A, Balducelli M, et al. Off-hour primary percutaneous coronary angioplasty does not affect outcome of patients with ST-Segment elevation acute myocardial
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Heart, Lung and Circulation (2019) xx, 1–10 1443-9506/04/$36.00 https://doi.org/10.1016/j.hlc.2019.05.184
ORIGINAL ARTICLE
The Impact of Out-of-Hours Presentation on Clinical Outcomes in ST-Elevation Myocardial Infarction Sinjini Biswas, MBBS a,b,1, Angela Brennan, RN a,1, Stephen J. Duffy, MBBS, PhD a,b, Nick Andrianopoulos, MBBS, MBiostat a, William Chan, MBBS, PhD b,c,k, Antony Walton, MBBS b, Samer Noaman, MBChB b, James A. Shaw, MBBS, PhD b, Andrew Ajani, MBBS, MD a,c,d, David J. Clark, MBBS, DMedSci e, Melanie Freeman, MBBS f, Chin Hiew, MBBS g, Ernesto Oqueli, MD h,i, Jeffrey Lefkovits, MBBS a,d, Christopher M. Reid, PhD a,j, Dion Stub, MBBS, PhD a,b,k* a
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic, Australia Department of Cardiology, The Alfred Hospital, Melbourne, Vic, Australia c Department of Medicine, University of Melbourne, Melbourne, Vic, Australia d Department of Cardiology, Royal Melbourne Hospital, Melbourne, Vic, Australia e Department of Cardiology, Austin Health, Melbourne, Vic, Australia f Department of Cardiology, Box Hill Hospital, Melbourne, Vic, Australia g Department of Cardiology, University Hospital Geelong, Geelong, Vic, Australia h Department of Cardiology, Ballarat Health Services, Ballarat, Vic, Australia i School of Medicine, Deakin University, Ballarat, Vic, Australia j School of Public Health, Curtin University, Perth, WA, Australia k Baker IDI Heart and Diabetes Institute, Melbourne, Vic, Australia b
Received 13 July 2018; received in revised form 26 March 2019; accepted 1 May 2019; online published-ahead-of-print xxx
Background
Systems of care have been established to ensure patients with ST-elevation myocardial infarction (STEMI) get timely access to primary percutaneous coronary intervention (PPCI). In this study, we evaluated whether patients undergoing PPCI both in-hours and out-of-hours experience similar care and clinical outcomes.
Methods
Of 9,865 patients who underwent PCI for STEMI from 2005 to 2016 and were enrolled in the multi-centre Melbourne Interventional Group registry, patients who had initially presented to a non-PCI capable hospital, received thrombolysis or presented >12 hours post-symptom onset were excluded. Our final study cohort of 4,590 patients were dichotomised by whether PPCI was performed in-hours or out-of-hours, and compared. The primary outcome was 30-day mortality.
Results
The in-hours group included 1,865 patients (40.6%) while 2,725 patients (59.4%) had out-of-hours PPCI. Patients presenting out-of-hours had longer median door-to-balloon time (DTBT; 83 [IQR 61–109] vs. 60 [IQR 41–88] mins, p < 0.01) and were more likely to receive a drug-eluting stent (p = 0.001). Procedural
*Corresponding author at: Department of Cardiology, The Alfred Hospital, Commercial Road, Melbourne, VIC 3004, Australia. Tel.: +61 3 9076 3263; Fax: +61 3 9076 2461, Email: [email protected] 1
Co-primary authors on manuscript.
© 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
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characteristics were otherwise similar although rates of radial access were low overall (18.4%). No differences in in-hospital, 30-day or 12-month mortality were observed between the groups (p = NS). On Cox proportional hazards modelling, out-of-hours presentation was not an independent predictor of 30-day mortality (HR 0.94, 95% CI 0.71–1.22). A landmark analysis of data from 2012 did not change the primary outcome.
Conclusion
Despite a slightly longer DTBT, patients undergoing PPCI out-of-hours experienced similar care and clinical outcomes to the in-hours group. Given the majority of patients with STEMI present out-of-hours, these data have implications for STEMI systems of care.
Keywords
ST-elevation myocardial infarction Primary percutaneous coronary intervention Outcomes Outof-hours presentation
Introduction In the last two decades, reperfusion of patients with STelevation myocardial infarction (STEMI) with urgent or primary percutaneous coronary intervention (PPCI) has become a mainstay of acute cardiac management. The importance of timely access to reperfusion with PPCI has been increasingly recognised with several analyses showing worsening survival in STEMI patients with longer door-to-balloon times [1,2]. As a result, robust systems of care have been developed in PCI-capable centres to allow for rapid mobilisation of oncall teams so that timely reperfusion can occur even when the patient presents outside of normal working hours. Some single-centre studies have demonstrated worse outcomes in patients undergoing PPCI outside of normal working hours compared to those treated in-hours [3]. This trend was also observed for cardiac patients admitted after-hours in general [4]. More recently, however, a subgroup analysis of the Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention (CHAMPION PHOENIX) study data showed no difference in in-hospital or 30-day major adverse cardiovascular events (MACE), which may reflect contemporary improvements in STEMI care [5]. Knowing whether differences exist in procedural factors and outcomes between in-hours and out-of-hours PPCI is crucial to improving the care of patients with STEMI. We therefore sought to determine whether there were any differences in reperfusion time, procedural characteristics or clinical outcomes between in- versus out-of-hours PPCI patients in a multi-centre Australian PCI registry.
Methods This was a retrospective cohort study of consecutive patients undergoing PPCI for STEMI from 1 January 2005 to 31 December 2016 inclusive, enrolled prospectively in the Melbourne Interventional Group (MIG) registry. PPCI was defined as urgent PCI in patients with STEMI who are within 12 hours of symptom onset. Patients who had PCI post thrombolysis and those who had inter-hospital transfer to a PCI-capable hospital were excluded. The MIG registry is a multi-centre PCI registry and has
previously been described in detail [6]. Briefly, demographic, clinical, procedural and in-hospital outcome data are prospectively recorded on case-report forms using standardised definitions for all fields with telephone follow-up and medical record review performed at 30 days and 12 months [7]. There are four participating hospitals located in metropolitan Melbourne and two hospitals in major regional cities in Victoria, that all have 24-hour cardiac catheterisation laboratory services. An audit of a number of verifiable fields from 5% of randomly selected procedures at each institution is undertaken periodically [8]. In the most recent audit, 27 fields were assessed with data accuracy of 98%. This compares favourably to audits from other large registries [9]. The primary ethics approval has been granted by the ethics committee at The Alfred Hospital (approval number 92/04), and also approved by each participating hospital, including the use of ‘‘opt-out” consent as previously described [7]. Patients were divided into two groups according to time of PPCI. Out-of-hours PPCI was defined by intervention performed during weekdays from 6 pm to 8 am and at any time during weekends and public holidays. In-hours PPCI was defined as procedures performed between 8 am to 6 pm on weekdays (excluding public holidays). Baseline and procedural characteristics, as well as short- and long-term clinical outcomes were compared between the two groups (definitions shown in Supplementary Table 1). The primary endpoint was 30-day mortality. Secondary endpoints included MACE and complications such as bleeding, stroke and target vessel revascularisation (TVR) during the index admission, and at 30-day and 12-month follow-up, in-hospital and 12month mortality, as well as door-to-balloon time (DTBT). MACE was defined as a composite of all-cause mortality, myocardial infarction and TVR. Only bleeding events that prolonged hospital stay and/or required a transfusion and/ or caused a fall in haemoglobin by >3.0 g/dL, were included. A landmark analysis of data from 2012 onwards was also performed to evaluate outcomes in a more contemporary study cohort. Continuous variables are expressed as mean standard deviation, and categorical data are expressed as numbers and percentages. Continuous variables were compared using the independent t-test or Mann-Whitney U test. Categorical variables were compared using Fisher’s exact test or Chi-square
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test as appropriate. The Kaplan-Meier method was used to estimate event-free survival rates and the log-rank test was used for survival comparisons. To determine whether out-ofhours PPCI was an independent predictor of 30-day mortality, in addition to out-of-hours PPCI, 28 other clinically relevant variables including gender, cardiovascular risk factors like diabetes mellitus and hypertension, history of previous MI, disease extent on angiography and lesion location for PPCI, were considered. Aside from the timing of PPCI variable which was forced into the model (HR 0.91, 95% CI 0.75–1.10, p = 0.33 on univariate analysis), only variables with a p value of <0.1 on univariate analysis that were not co-linear were entered into a stepwise backward selection modelling process for multivariable assessment. Cox proportional hazards modelling (log likelihood = -1,569.5) was used in this study. While the model failed the proportional hazards assumption when the timing of PPCI variable (out-ofhours vs. in-hours) was forced into the model (global test p = 0.003), the proportional hazards assumption was satisfied when this variable was excluded (global test p = 0.107). Given this finding as well as the similarities seen in the results of a multivariable logistics regression model and the Cox proportional hazards model, further modelling was not performed as it would be unlikely for such models to show a significant association between out-of-hours PPCI and 30-day mortality hazard. Complete case analysis was performed for purposes of multivariable modelling (i.e. patients with missing values were excluded). All statistical analyses were performed using Stata 13.1 software (StataCorp LP, College Station, TX, USA). A twosided p value of <0.05 was considered statistically significant.
Results In total, 9,865 patients underwent PCI for STEMI at the participating hospitals in the registry. Of these patients, 1,133 patients had received thrombolysis prior to PCI, 2,092 patients had initially presented to a non-PCI capable hospital, and 2,050 patients had presented with symptom onset >12 hours prior and did not meet our definition of PPCI, and therefore were excluded (Figure 1). Consequently, the study cohort included 4,590 patients who underwent PPCI for STEMI during the study period and met our inclusion criteria. Of these, 1,865 patients (40.6%) were treated inhours and 2,725 patients (59.4%) were treated out-of-hours. Overall, the mean age was 63.1 12.7 years and 3,637 patients (79.2%) were male. Table 1 shows the baseline demographics and clinical presentation of the two groups. Patients in the out-of-hours group were younger (62.1 12.6 years vs. 64.6 12.6 years, p < 0.001). The two groups were otherwise very similar in baseline demographics, cardiovascular risk factors and presentation characteristics. There were also no major differences in procedural characteristics such as access route, lesion complexity and proportion of unsuccessful PCI procedures, between the two groups (all p > 0.05) (Table 2). However, drug-eluting stent (DES) use was higher in the out-of-hours PPCI group (43.5% vs. 38.5%, p < 0.001). In terms of times to presentation, median symptom-todoor time (STDT) was slightly shorter in the out-of-hours group compared to the in-hours group (95 [IQR 65–148] mins vs. 100 [IQR 67–155] mins, p = 0.04) (Table 1). However, the proportion of cases in which pre-hospital notification was received was significantly lower in the out-of-hours group
Figure 1 Consort Diagram for Cohort Selection. Abbreviations: PCI, percutaneous coronary intervention; MIG, Melbourne Interventional Group; STEMI, ST-elevation myocardial infarction.
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Table 1 Baseline Demographic & Clinical Characteristics. PPCI in-hours
PPCI out-of-hours
P-value
1,865 64.6 12.6
2,725 62.1 12.6
– <0.001
1,458 (78.2%)
2,179 (80.0%)
0.14
27.5 4.9
28.1 5.1
0.98
307 (16.5%)
450 (16.5%)
0.96
Hypertension
1,015 (54.5%)
1,395 (51.3%)
0.03
Dyslipidaemia
893 (48.1%)
1,311 (48.2%)
0.94
Current/previous smoker
1,172 (64.3%)
1,736 (65.2%)
0.53
Estimated glomerular filtration rate > 60 ml/min/1.73m2 Estimated glomerular filtration rate 30 – 60 ml/min/1.73m2
1,178 (74.7%) 359 (22.8%)
1,809 (72.8%) 621 (25.0%)
0.22
Number of patients Mean age SD (years) Male Mean body mass index SD (kg/m2) Diabetes mellitus
Estimated glomerular filtration rate < 30 ml/min/1.73m
2
41 (2.6%)
55 (2.2%)
Previous myocardial infarction
235 (12.6%)
340 (12.5%)
0.92
Family history of coronary artery disease
556 (31.2%)
926 (35.8%)
0.002
Previous heart failure (>2 weeks prior)
30 (1.6%)
40 (1.5%)
0.70
Previous stroke
86 (4.6%)
119 (4.4%)
0.69
Peripheral vascular disease
53 (2.9%)
86 (3.2%)
0.54
149 (8.0%) 213 (11.4%)
233 (8.6%) 290 (10.7%)
0.50 0.40
Chronic obstructive pulmonary disease Prior percutaneous coronary intervention Prior coronary artery bypass graft surgery
43 (2.3%)
56 (2.1%)
0.56
Post out-of-hospital cardiac arrest
218 (11.7%)
320 (11.7%)
0.96
Cardiogenic shock
214 (11.5%)
296 (10.9%)
0.52
95 [IQR 65–148]
100 [67–155]
0.04
60 [41–88]
83 [61–109]
<0.001
168 [128–239]
188 [147–248]
<0.001
1,440 (77.5) 524 (55.5)
1,581 (58.3) 718 (48.1)
<0.001 <0.001
Symptom-to-door time (minutes), median [IQR] Door-to-balloon time (minutes), median [IQR] Symptom-to-balloon time (minutes), median [IQR] Door-to-balloon time <90 minutes Pre-hospital notification received Abbreviation: PPCI, primary percutaneous coronary intervention.
(48.1% vs. 55.5%; p < 0.001) and median DTBT was significantly longer in the out-of-hours group compared to the inhours group (83 [IQR 61–109] mins vs. 60 [IQR 41–88] mins; p < 0.001). In addition, the proportion of patients achieving the target DTBT less than 90 minutes was also significantly lower in the out-of-hours group (58.3% vs. 77.5%, p < 0.001). Consequently, median total ischaemic time (i.e. STBT) was longer in those undergoing PPCI out-of-hours, compared to inhours (188 [IQR 147–248] mins vs. 168 [128–239] mins, p < 0.001). Similar differences in STDT, DTBT and STBT were seen by time of presentation in both metropolitan and regional hospitals in our registry (Supplementary Table 2). Over the 12-year study period, DTBT for both the groups has steadily fallen over the period (both p for trend <0.001) (Supplementary Figure 1). In contrast, median STDT has remained relatively stable in the in-hours group, while it has increased over time in the out-of-hours group (p for trend <0.001) (Supplementary Figure 2). Table 3 shows a comparison of in-hospital, 30-day and 12month outcomes between the two groups. A total of 323 patients (7.0%) in the study died during the index hospital admission. There was no significant difference in in-hospital
mortality or MACE between the two groups (6.8% vs. 7.4%, p = 0.50 and 9.6% vs. 9.8%, p = 0.87 respectively). There were also no significant differences in 30-day and 12-month mortality or MACE between the two groups. In addition, no significant difference in use of dual antiplatelet therapy (DAPT) was seen at 30 days post-PCI, although there was a trend towards lower use of DAPT in the in-hours cohort at 12 months. Overall, there was no change in 30-day mortality or MACE rates over the study period (p for trend = 0.19 and 0.14 respectively [Supplementary Table 3]). The rates of other complications such as major bleeding, peri-procedural myocardial infarction and target vessel revascularisation were similar in both groups during the index hospital admission, as well as at 30-day and 12-month follow-up (all p > 0.05). The 30-day and 12-month readmission rates were also similar between the two groups (both p > 0.05). Similar results were seen regardless of whether the patient was treated at a metropolitan or regional hospital, with no differences in in-hospital, 30-day or 12-month outcomes (all p > 0.05) (Supplementary Table 2). In a Cox proportional hazards model, the three strongest independent predictors of 30-day mortality were found to be
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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Table 2 Angiographic and Procedural Characteristics. PPCI in-hours
PPCI out-of-hours
P-value
1,865 327 (17.5%)
2,725 518 (19.0%)
0.23
1,536 (82.4%)
2,200 (80.7%)
Single vessel disease
870 (46.7%)
1,253 (46.0%)
Multi-vessel disease
995 (53.4%)
1,470 (54.0%)
Number of patients Radial access Femoral access
-
Extent of coronary disease: 0.67
Ostial lesion
149 (6.9%)
242 (7.7%)
0.28
Bifurcation lesion
237 (10.9%)
358 (11.3%)
0.65
1,568 (72.3%) 13 (0.6%)
2,239 (70.9%) 31 (1.0%)
0.26 0.13
30 (1.6%)
48 (1.8%)
0.69
AHA/ACC Type B2/C lesion Left main percutaneous coronary intervention Multi-vessel percutaneous coronary intervention TIMI flow grade pre- percutaneous coronary intervention TIMI 0 flow
1,442 (66.7%)
2,040 (64.7%)
TIMI 1 flow
99 (4.6%)
188 (6.0%)
TIMI 2 flow
238 (11.0%)
305 (9.7%)
TIMI 3 flow
0.02
384 (17.8%)
620 (19.7%)
TIMI 3 flow post- percutaneous coronary intervention Thrombectomy device
2,016 (93.0%) 522 (27.2%)
2,954 (93.6%) 731 (25.5%)
0.44 0.19
Glycoprotein IIb/IIIa inhibitor
0.70
1,270 (68.1%)
1,869 (68.6%)
Intra-aortic balloon pump
122 (9.2%)
184 (10.0%)
0.46
Drug-eluting stent
717 (38.5%)
1,186 (43.5%)
0.001
Acute complications: Acute closure
24 (1.1%)
18 (0.6%)
0.03
Dissection
99 (4.6%)
93 (2.9%)
0.002
Perforation Transient/persistent no-reflow
5 (0.2%) 140 (6.5%)
11 (0.4%) 158 (5.0%)
0.44 0.02
Unsuccessful percutaneous coronary intervention
97 (4.5%)
130 (4.1%)
0.52
1,126 (64.9%)
1,607 (62.8%)
570 (32.9%)
886 (34.6%)
39 (2.3%)
67 (2.6%)
Left ventricular ejection fraction: Left ventricular ejection fraction >45% Left ventricular ejection fraction 30–45% Left ventricular ejection fraction <30%
0.33
Abbreviation: PPCI, primary percutaneous coronary intervention.
presentation with cardiogenic shock (HR 4.49, 95% CI 3.25– 6.19, p < 0.001), severe left ventricular systolic dysfunction defined as a left ventricular ejection fraction (LVEF) <30% (HR 4.06, 95% CI 2.66–6.20, p < 0.001) and stage 4–5 chronic kidney disease (HR 3.97, 95% CI 2.49–6.34, p < 0.001) (Table 4). Out-of-hours PPCI was not found to be an independent predictor of 30-day mortality (HR 0.94, 95% CI 0.71–1.22, p = 0.63). Kaplan-Meier survival curves are shown in Figure 2 and Supplementary Figure 3. These demonstrated that while 30-day survival was worse in the in-hours group (log-rank p = 0.02) there was no difference in long-term survival between the outof-hours and in-hours PPCI groups (log-rank p = 0.43). When patients with cardiogenic shock and presentation post-OHCA were excluded, the three strongest predictors of 30-day mortality in a Cox proportional hazards model were found to be severe left ventricular systolic dysfunction defined as LVEF < 30% (HR 11.32, 95% CI 7.51–17.06, p < 0.001), stage 4–5 chronic kidney disease (HR 7.51, 95% CI
4.81–11.74, p < 0.001) and stage 3 chronic kidney disease (HR 3.30, 95% CI 2.44–4.47, p < 0.001) (Supplementary Table 4). A DTBT<90 minutes was found to be an independent protective factor (HR 0.71, 95% CI 0.54–0.93, p = 0.01). Out-of-hours PPCI was again not found to be an independent predictor of 30-day mortality (HR 0.80, 95% CI 0.61–1.05, p = 0.11). In a landmark analysis of data from 2012 onwards, median door-to-balloon time continued to be significantly longer in the out-of-hours PPCI group (74 [IQR 55–99] mins vs. 51 [IQR 37– 76] minutes, p < 0.001) and the proportion of patients achieving a DTBT<90 minutes in the out-of-hours PPCI group was also lower (67.2% vs. 83.1%, p < 0.001) (Supplementary Table 5). Drug eluting stent (DES) use was higher and importantly equivalent in the out-of-hours and in-hours PPCI groups (55.1% vs. 52.4%, p = 0.30) (Supplementary Table 6). However, in-hospital, 30-day and 12-month outcomes were again similar between the in-hours and out-of-hours PPCI groups (Supplementary Table 7) (all p > 0.05). In a Cox proportional hazards
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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Table 3 In-Hospital, 30-Day and 12-Month Outcomes. PPCI in-hours
PPCI out-of-hours
P-value
IN-HOSPITAL Death
137 (7.4%)
186 (6.8%)
0.50
Peri-procedural myocardial infarction
22 (1.2%)
39 (1.4%)
0.47
Target vessel revascularisation
44 (2.4%)
75 (2.8%)
0.41
Major adverse cardiovascular events
182 (9.8%)
262 (9.6%)
0.87
Major bleeding
83 (4.5%)
116 (4.3%)
0.75
15 (0.9)
19 (0.8)
0.63
150 (8.0%) 34 (1.8%)
201 (7.4%) 55 (2.0%)
0.40 0.64
Stent thrombosis 30-DAY Death Myocardial infarction Target vessel revascularisation
54 (2.9%)
100 (3.7%)
0.15
Major adverse cardiovascular events
213 (11.4%)
306 (11.2%)
0.84
Readmission
226 (13.2%)
367 (14.6%)
0.21
16 (1.0)
19 (0.8)
0.64
1,537 (93.8)
2,285 (93.8)
0.97
183 (11.9%) 68 (4.4%)
241 (11.1%) 92 (4.2%)
0.45 0.78
Stent thrombosis Use of dual antiplatelet therapy 12-MONTH Death Myocardial infarction Target vessel revascularisation
119 (7.7%)
182 (8.4%)
0.48
Major adverse cardiovascular events
324 (21.0%)
436 (20.0%)
0.46
Readmission
470 (34.7%)
692 (35.8%)
0.42
834 (66.7)
1,244 (70.1)
0.05
Use of dual antiplatelet therapy Abbreviation: PPCI, primary percutaneous coronary intervention.
Table 4 Independent Predictors of 30-Day Mortality. Hazard ratio
95% Confidence Interval
P-value
Left ventricular ejection fraction Left ventricular ejection fraction >45%
1 (ref)
Left ventricular ejection fraction 30–45%
2.14
1.57–2.92
<0.001
Left ventricular ejection fraction <30%
4.06
2.66–6.20
<0.001
Estimated glomerular filtration rate (eGFR) eGFR >60 ml/min/1.73m2
1 (ref)
eGFR 30–60 ml/min/1.73m2
2.10
1.56–2.83
<0.001
eGFR <30 ml/min/1.73m2
3.97
2.49–6.34
<0.001
Out-of-hospital cardiac arrest
3.85
2.84–5.22
<0.001
Cardiogenic shock
4.49
3.25–6.19
<0.001
Chronic lung disease
1.58
1.09–2.30
0.02
Hypertension
1.60
1.19–2.15
0.002
Age (per year increase) Time of primary percutaneous coronary intervention (PPCI)
1.03
1.02–1.04
<0.001
In-hours PPCI
1 (ref)
Out of hours PPCI
0.94
0.71–1.22
0.63
Drug-eluting stent use
0.68
0.50–0.91
0.01
PPCI to right coronary artery lesion
0.47
0.34–0.65
<0.001
Abbreviations: eGFR, estimated glomerular filtration rate; PPCI, primary percutaneous coronary intervention.
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Figure 2 Kaplan-Meier curves of short-term survival for patients undergoing in-hours vs. out-of-hours primary PCI for STEMI. Abbreviations: PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
model, out-of-hours PPCI was not found to be an independent predictor of 30-day mortality in this more contemporary cohort of patients (Supplementary Table 8).
Discussion This large, multi-centre study of consecutive patients with STEMI undergoing PPCI showed that patients undergoing PPCI out-of-hours had a longer median DTBT while fewer patients achieved the target DTBT of less than 90 minutes when PPCI was performed out-of-hours. However, the magnitude of the delay in reperfusion in patients undergoing outof-hours PPCI had no significant impact on key clinical outcomes including in-hospital and 30-day mortality. Even when patients with cardiogenic shock and those post outof-hospital-cardiac-arrest (OHCA) at presentation were excluded, out-of-hours PPCI was not independently associated with 30-day mortality. Over the study period, while median DTBT for both in-hours and out-of-hours PPCI has significantly fallen, the difference in times between the two groups has not changed significantly. Consequently, total ischaemic time has remained longer in the out-of-hours group compared to in-hours. Despite improvements in PCI practice including stent technology and antiplatelet therapy over the study period, there has been no overall change in 30-day mortality, both for in-hours and out-of-hours PPCI. Overall, patients undergoing PPCI receive similar care regardless of time of presentation. There are many reasons why the outcomes of PPCI may differ in patients presenting outside normal working hours including potential differences in patients’ baseline characteristics or procedural factors such as the use of adjunctive
therapies and rates of complications. A circadian variation in the efficacy of fibrinolytic therapy to re-establish flow in coronary arteries with acute thrombotic occlusion has been described, most likely due to alterations in the balance between prothrombotic factors and intrinsic fibrinolytic factor at different times of day [10]. In particular, levels of natural fibrinolytic factors have been shown to be higher in the evening hours while platelet aggregation is increased in the early morning hours [11,12]. While these findings are mostly based on studies performed in patients treated with thrombolysis, they may still be relevant in a PPCI cohort like ours with respect to the how easily antegrade flow can be restored in the infarct-related artery out-of-hours. Apart from patients in the out-of-hours group being slightly younger, the two groups in our study were quite well-matched in terms of baseline and procedural characteristics. In contrast to some other studies, the proportions of high-risk STEMI patients presenting with cardiogenic shock or post-OHCA were also similar between the two groups, as was the extent of disease and lesion complexity found on angiography [13]. However, the proportion of patients with cardiogenic shock undergoing PCI in our study overall was high when compared to other PCI registries (e.g. <3% in the Swedish Coronary Angiography and Angioplasty Registry in 2012 vs. 10.0% in the MIG registry in 2012), which may explain our relatively high rates of 12-month mortality and MACE [14]. Drug eluting stent use was higher in the out-of-hours group, although the absolute magnitude of difference was small and potentially related to operator preference at hospitals that perform more out-of-hours PPCI. DES use has also increased over time and in patients treated from 2012 onwards, DES use was similar between the two groups. Of note, DES use was found to be protective on multivariable analysis while increased age and
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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history of hypertension were independent risk factors. The higher DES use in the out-of-hours group along with these patients being younger and less likely to have hypertension may explain to an extent why outcomes in the out-of-hours group were not inferior to the in-hours group. Overall, the proportion of patients having an unsuccessful PCI or post-PCI TIMI flow <3 were similar in both groups. This suggests no deterioration in the quality of PPCI when it was performed outof-hours, which could be expected as a result of factors such as operator fatigue [13]. The significant differences in reperfusion times between inhours and out-of-hours PPCI seen in our study is similar to previous reports [15,16,17,18,19]. While median DTBT has fallen over the study period in both groups, overall it was still 23 minutes longer in the out-of-hours group compared to the inhours group. Despite this treatment delay, our study showed no difference in in-hospital or intermediate-term mortality between the in-hours and out-of-hours PPCI groups. Previous studies have shown that a 30-minute delay in DTBT is associated with a 20–30% relative increase in in-hospital mortality regardless of baseline DTBT [1,2,20]. This suggests that, given the significant improvements in DTBT that have already been made by incorporating strategies such as pre-hospital ambulance notification of STEMI and streamlined STEMI on-call teams, as well as improved stent technology and adjunctive pharmacotherapy, there may be little clinical benefit from trying to reduce the small inherent delay in out-of-hours cases any further with more expensive and resource-intensive measures such as having on-call STEMI teams stay on site outside of working hours, as is used in certain hospital systems [21,22,23]. Many previous studies, which have shown a mortality hazard in patients with acute myocardial infarction admitted on weekends or out-of-hours, have, in general included a heterogeneous patient population, including those treated with thrombolysis [24,25,26,27,28]. In contrast, studies that have included patients with STEMI treated by PPCI only, including a recent meta-analysis of 86,776 patients from 39 studies, have shown similar results to ours with no difference in both inhospital and longer-term mortality regardless of timing of PPCI [29,30,31,32,33,34,35,36]. Our study also showed no differences in rates of recurrent MI or target vessel revascularisation between the two groups. While there was also no difference in in-hospital bleeding between the two groups, we did, however, note that rates of bleeding complications in our study were higher overall when compared to similar contemporary studies [29]. This may be due to the higher proportion of femoral access cases in our cohort, as well as the use of different definitions of bleeding. Indeed, our analysis of data from 2012 onwards demonstrated a higher proportion of radial access cases as well as a slight drop in rates of bleeding complications, a trend which we expect to see continue. In our study, we noted that median STDT was shorter by 5 minutes in the out-of-hours group compared to the in-hours group. This has also been reported in other studies, and may have occurred as patients with cardiac symptoms may initially present to other health care services that are available during working hours such as their primary care physician,
rather than presenting directly to an emergency department or calling an ambulance, leading to delays in STDT [37,38]. We also noted that patients presenting out-of-hours were more likely to have pre-hospital notification by ambulance services, which may have an impact on STDT. Unfortunately, there was no significant improvement in STDT over the study period, and of particular concern was the increasing median STDT seen in the out-of-hours group over time in our study (Supplementary Figure 2). Overall, only 20.7% of patients in our study presented within the first hour of onset of symptoms, regardless of time of procedure, indicating that increased focus needs to be placed in improving community awareness of early warning signs of myocardial infarction (MI) and the appropriate action plan. Media campaigns have been shown to have an impact on reducing delays to presentation and could be utilised further in the future [39]. Our study had a number of limitations. This was a retrospective analysis of patients enrolled prospectively in a PCI registry, which brings its own inherent limitations including an inability to account for all confounders. Secondly, our study may not have been powered to detect a difference in survival given the small difference in DTBT between the groups. Other studies have shown that such a difference in DTBT may result in more long-term left ventricular dysfunction and heart failure readmissions, but not be enough to cause mortality hazard [40,41]. Our study did not evaluate for differences in infarct size or long-term left ventricular dysfunction between out-of-hours and in-hours PPCI, which would be important to assess in future work. Thirdly, our study had a long inclusion period, during which time, PPCI practice has evolved. Therefore, to an extent, our study reflects outcomes in a historical cohort of patients. However, outcomes after PPCI have remained unchanged over this study period suggesting that our results are still applicable to contemporary PPCI patients. In addition, a landmark analysis of data from 2012 onwards did not show any significant difference in results. Finally, we only included patients undergoing PPCI; therefore, these results may not be generalisable to patients with STEMI who receive medical management only or undergo PCI post-thrombolysis. In conclusion, this large, multi-centre observational realworld study demonstrates that, despite a small increase in door to balloon time, there is no difference in mortality or MACE following PPCI whether it is performed in-hours or out-of-hours. Our findings reassuringly demonstrate consistent procedural and clinical quality across multiple PPCI centres regardless of time of presentation. While hospitals should continue to improve processes to minimise delays to PPCI, the small inherent delays that occur for out-of-hours cases are not long enough to adversely affect outcomes in these patients.
Funding and Disclosures We would like to acknowledge the following sources of scholarship/grant support: The National Heart Foundation
Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184
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of Australia (Dr Biswas: reference no. 101518; Dr Stub: reference no. 101908), the National Health and Medical Research Council of Australia (Professor Duffy: reference no. 1111170, Dr Chan: reference no. 1052960, Professor Reid: reference no. 1045862), the Australian Government Research Training Program (Dr Biswas) and the Viertel Foundation (Dr Stub). The Melbourne Interventional Group acknowledges funding from Abbott, Astra-Zeneca, Medtronic, MSD, Pfizer, Servier and The Medicines Company. These companies do not have access to data and do not have the right to review manuscripts or abstracts before publication.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.hlc. 2019.05.184.
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Please cite this article in press as: Biswas S, et al. The Impact of Out-of-Hours Presentation on Clinical Outcomes in STElevation Myocardial Infarction. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2019.05.184