Prehospital Transfer Pathway and Mortality in Patients Undergoing Primary Percutaneous Coronary Intervention

Abstract

Background: It is recommended that not only door-to-balloon time but also prehospital delay for primary percutaneous coronary intervention (PCI) should be improved. We investigated the effect of prehospital transfer pathway on onset-to-balloon time and prognosis in patients with ST-segment elevation myocardial infarction (STEMI) in Japan.

Methods and Results: We analyzed data from 540 consecutive patients with primary PCI for STEMI. Patient clinical data and mortality were compared between patients who visited the family physician or non-PCI-capable hospitals and were then transferred to PCI-capable centers (indirect transfer patients), and those who directly visited PCI-capable centers (direct transfer patients). Onset-to-balloon time was longer in indirect transfer patients than in direct transfer patients (mean, 270 min; range, 180–480 min vs. 180 min, 120–240 min; P<0.001). In addition, patient prognosis was evaluated on Cox proportional regression analysis. Cardiac death and all-cause death were significantly higher in indirect transfer patients (odds ratios [OR], 2.17; 95% confidence intervals [95% CI]: 1.17–4.01, P=0.01; OR, 1.71; 95% CI: 1.09–2.68, P=0.02). These results were confirmed using propensity score matching for adjusted analyses.

Conclusions: Patients with indirect transfer to regional emergency departments of PCI centers had longer onset-to-balloon time and worse prognosis than those with direct transfer. (Circ J 2015; 79: 2000–2008)

Primary percutaneous coronary intervention (PCI) is recommended in patients with ST-segment elevation myocardial infarction (STEMI). PCI is superior to fibrinolytic therapy for reducing mortality, reinfarction, and stroke,^1,2 but primary PCI must be performed in a timely manner to be effective. Previous studies have shown that the viability of cardiomyocytes is markedly decreased within 3 h after the onset of acute myocardial infarction (AMI).^3,4 The total time between the onset of symptoms and primary PCI, termed treatment delay, has several components. In this study, we referred to the previously used definition concerning the time between onset and reperfusion (Figure 1).⁵

Figure 1.

Time between onset and reperfusion. Door-to-balloon time was defined as the time between arrival at a percutaneous coronary intervention (PCI)-capable hospital and the first balloon inflation. Onset-to-balloon time was defined as the time from onset of symptoms to the first balloon inflation. System delay was defined as the time from the first contact with the health-care system to reperfusion, which includes prehospital delay, time in the emergency room (ER), and time in the catheterization room.

Editorial p 1897

Current guidelines recommend that not only door-to-balloon time but also the first medical contact-to-balloon time should be improved.^6,7 In particular, the manner of patient transfer is considered to be a reason for treatment delay.⁸ Recently, a Canadian cohort study reported that a STEMI system that allowed emergency medical services to transfer patients directly to a primary PCI center was associated with prompt reperfusion and reduced mortality.^9,10 Primary PCI has generally been the dominant strategy for reperfusion therapy for AMI in Japan,^11–14 but how rapidly such reperfusion therapy is achieved remains unclear.

We hypothesized that AMI patients who visited regional PCI-capable centers via family physician offices or non-PCI-capable hospitals have worse outcome than patients who directly visit PCI-capable centers because of the treatment delay caused by the additional transfer time.

Methods

Patients

Between June 2003 and September 2010, 637 consecutive patients underwent emergency PCI for AMI at the Department of Cardiology and Catheter Laboratories, Shonan Kamakura General Hospital (Kamakura, Japan). Of these, 540 underwent primary PCI for STEMI within 12 h of the onset of symptoms and were eligible for inclusion in the study. Diagnosis was made on the basis of typical lasting chest pain and admission electrocardiogram (ECG) changes (ST-segment elevation in at least 2 adjacent leads). Emergency coronary angiography and primary PCI were performed using standard techniques. Individual physicians decided on the treatment strategies used for each patient. All diagnoses of AMI were confirmed on increase of cardiac enzymes above the normal range. Patients were excluded if they underwent out-of-hospital cardiac arrest. Written informed consent was obtained from all patients, and ethics approval was obtained from the Review Committee of Shonankamakura General Hospital, Japan.

Data Analysis and Definitions

Data were collected from uniform case report databases and medical records. The following data were collected: patient age, sex, Killip class, family history, onset-to-balloon time, door-to-balloon time, patient transfer pathway, status with regard to diabetes mellitus (DM), hypertension (HT), smoking, chronic kidney disease (CKD), previous MI, PCI procedures and devices, laboratory data, ejection fraction measured on transthoracic echocardiogram after reperfusion (baseline) and at 6-month follow-up, and the occurrence of complications and death.

The presence and severity of coronary atherosclerotic lesions was determined on visual estimation or using a quantitative coronary angiography program at the discretion of the angiographer. Coronary artery lesions, graded on the basis of the narrowing of the lumen diameter in a major epicardial artery or one of its major branches, were classified as significant coronary artery disease if narrowing was ≥75% for the left anterior descending artery, left circumflex artery, and right coronary artery or ≥50% for the left main trunk.¹⁵ Multivessel disease was defined as more than 2 involved vessels, and left main disease was diagnosed as significant stenosis of the left main trunk, with or without concomitant lesions in other vessels. Onset-to-balloon time was defined as the interval from the onset of symptoms of ischemia to the first balloon inflation or device delivery. Door-to-balloon time was defined as the interval from arrival at the hospital where emergency PCI was performed (not the arrival time at the referral hospitals for transferred patients) to the first balloon inflation or device delivery. Patients were divided into 2 groups according to the prehospital transfer pathway, and the baseline characteristics, time factor, and clinical outcomes were then compared between the 2 groups. The first group consisted of patients who visited the family physician or non-PCI-capable hospitals and were then transferred to the PCI-capable centers (indirect transfer patients), whereas the second group consisted of patients who directly visited the PCI centers (direct transfer patients).

Statistical Analysis

Continuous variables are presented as mean±SD or median (IQR). For univariate analysis between groups, continuous variables were compared using Student’s 2-sample t-test. Categorical variables were assessed using Fisher’s exact test or nonparametric analysis for non-normally distributed data.

Multivariate analysis was performed to assess the independent effect of transfer pathway on mortality. The cumulative incidence of cardiac or all-cause death was calculated using the Kaplan-Meier method. Differences between groups were analyzed using stratified log-rank test on the matched pairs. Cox regression models were used to fit the variables that were related to prognosis on univariate analysis (P<0.15 for the transfer pathway, age, sex, family history, DM, HT, smoking status, CKD, history of previous MI, anterior MI, left main disease, Killip class, multivessel disease, intra-aortic balloon pumping, transradial coronary intervention, temporary pacing, thrombus aspiration, and stent implantation). We excluded onset-to-balloon time and door-to-balloon time because of their relationship with direct and indirect transfer. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using Cox regression models. We also constructed a second model using propensity score (PS) matching for adjusted analyses. PS were estimated using the baseline patient characteristics (age, sex, family history, DM, HT, smoking status, CKD, history of previous MI, left main disease, Killip class, and multivessel disease) as predictors in logistic regression models with direct or indirect transfer as the outcome. The discrimination of the PS model was assessed using the Hosmer-Lemeshow test and C-statistics. PS matching was performed using the following algorithm: nearest neighbor and 1-to-1 pair matching with a ±0.01 caliper and no replacement. Absolute standardized difference (ASD) was used to measure covariate balance, and ASD>10% represented imbalance. In this model, the cumulative incidences of cardiac or all-cause death were calculated using the Kaplan-Meier method, and differences between groups were analyzed using a stratified log-rank test on the matched pairs. For all analyses, 2-tailed P<0.05 was considered to be statistically significant. SPSS (SPSS, Chicago, IL, USA) was used for analysis.

Results

Patient Characteristics

In total, 540 patients (72% male) were enrolled in the study. Among these, 160 (30%) were indirect transfer patients, while 380 (70%) were direct transfer patients. Indirect transfer patients consisted of individuals who visited the family physician or non-PCI-capable hospitals first. Mean patient age was 69±13 years, and demographic data and clinical features are presented in Table 1. The baseline characteristics were similar in the 2 groups, but indirect transfer patients were less likely to have a history of MI (5% vs. 10%, P=0.05). Patients in this group were also more likely to be male (65% vs. 75%, P=0.02) and elderly (72±12 vs. 67±13 years, P<0.001).

Table 1. Subject Characteristics (n=540)

	Indirect transfer, n=160 (30%)	Direct transfer, n=380 (70%)	P-value
Age (years)	72±12	67±13	<0.001
Male	104 (65)	285 (75)	0.02
DM	51 (32)	99 (26)	0.17
HT	72 (45)	194 (51)	0.20
Smoking	53 (33)	150 (40)	0.16
CKD	64 (40)	145 (38)	0.70
Family history	17 (11)	43 (11)	0.86
Previous MI	8 (5)	39 (10)	0.05
Killip class III/IV	24 (15)	59 (16)	0.88
Stenting performed	153 (96)	360 (95)	0.67
Total stent length (mm)	24±9	22±9	0.11
Stent diameter (mm)	3.26±0.38	3.28±0.41	0.57
No. stents per patient	1.2±0.5	1.2±0.6	0.41
Multi-vessel disease	59 (40)	166 (44)	0.14
Left main disease	6 (3.8)	28 (7.4)	0.11
Trans-radial approach	138 (86)	332 (88)	0.61
IABP	29 (18)	77 (20)	0.57
Thrombus aspiration	138 (86)	320 (84)	0.59
Temporary pacing	46 (29)	100 (26)	0.56
Culprit lesion			0.62
Left main trunk	4 (3)	11 (3)	–
RCA	69 (43)	157 (41)	–
LAD	69 (43)	171 (45)	–
LCX	17 (11)	41 (11)	–
Bypass graft	1 (1)	0 (0)	–
TIMI flow grade 3	143 (90)	359 (95)	0.06
Blush score 3	51 (46)	175 (61)	0.005
Onset-to-balloon time (min)	270 (180–480)	180 (120–240)	<0.001
Door-to-balloon time (min)	62 (45–84)	68 (52–87)	0.02
Prehospital delay (min)	203 (123–394)	84 (50–154)	<0.001
Onset-to-balloon time <180 min	55 (34)	244 (64)	<0.001

Data given as mean±SD, median (IQR) or n (%). DM, HT, and CKD were diagnosed by the attending physician according to current guidelines. CKD, chronic kidney disease; DM, diabetes mellitus; HT, hypertension; IABP, intra-aortic balloon pumping; LAD, left anterior descending artery; LCX, left circumflex; MI, myocardial infarction; RCA, right coronary artery; TIMI, Thrombolysis in Myocardial Infarction.

Procedures and Clinical Outcomes

Emergency coronary angiography and primary PCI were performed in all patients. The angiographic and procedural results are listed in Table 1. Onset-to-balloon time was longer in indirect transfer patients than in direct transfer patients (mean, 270 min; range, 180–480 min vs. 180 min, 120–240 min; P<0.001; Figures 1,2). Prehospital delay was longer in indirect transfer patients than in direct transfer patients (mean, 203 min; range, 123–394 min vs. 84 min, 50–154 min; P<0.001; Figure 1). The prevalence of onset-to-balloon time <3 h was lower in indirect transfer patients than in direct transfer patients (34% vs. 64%, P<0.001; Figure 1). In contrast, door-to-balloon time was shorter in indirect transfer patients than direct transfer patients (mean, 62 min; range, 45–84 min vs. 68 min, 52–87 min; P=0.02; Figures 1,2). In the direct transfer patients, 75% were directly transferred to the PCI center by ambulance, whereas 25% used self-transport (Table S1). Onset-to-balloon time, prehospital delay, and door-to-balloon time were shorter in patients who transferred directly by ambulance than by self-transport (mean, 180 min; range, 120–240 min vs. 210 min, 180–360 min, P<0.001; 84 min, 50–154 min vs. 131 min, 63–251 min, P<0.001; and 62 min, 45–84 min vs. 68 min, 52–87 min, P=0.02; respectively, Table S1).

Figure 2.

Patient transfer and delay. Onset-to-balloon time in (blue) indirect transfer patients was longer than in the (orange) direct transfer patients, while door-to-balloon time was shorter.

There were no differences in the procedures used between groups. Indirect transfer patients had less satisfactory reperfusion flow than direct transfer patients according to prevalence of Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 (90% vs. 95%, P=0.06), and blush score of 3 (46% vs. 61%, P=0.005; Table 1). There was a significant difference in the peak creatine kinase (CK)-MB level (mean, 217 IU; range, 112–422 IU vs. 162 IU, 76–337 IU, P=0.01) but no difference in peak CK between the indirect and direct transfer patients (mean, 2,327 IU; range, 1,169–4,538 IU vs. 2,055 IU, 944–4,083 IU; P=0.12; Figure 3). Indirect transfer patients had a decreased 6-month left ventricular ejection fraction (LVEF; 56±11% vs. 60±12%, P=0.01), but there was no difference in the change in LVEF from baseline to 6 months (5±17% vs. 5±18%, P=0.99), although follow-up data were available for only 75% of patients.

Figure 3.

Creatine kinase (CK)-MB was higher and there was a trend toward increasing CK in indirect transfer patients compared with direct transfer patients.

Predictors of Long-Term Mortality

In the first analysis, patient prognosis was evaluated using Cox proportional regression analysis. Cardiac death (Figures 4A,5A) and all-cause death (Figures 4B,5B) were significantly higher in indirect transfer patients (OR, 2.17; 95% CI: 1.17–4.01, P=0.01 and OR, 1.71; 95% CI: 1.09–2.68, P=0.02, respectively). Age, Killip class, and left main disease were also independent predictors of cardiac death. Age, prior MI, and Killip class were independent predictors of all-cause death. In a second analysis to adjust for PS, cardiac mortality was higher in indirect transfer patients than in direct transfer patients (P=0.04, Figure 6A). All-cause mortality tended to be higher in indirect transfer patients than in direct transfer patients (P=0.08, Figure 6B). Hosmer-Lemeshow test C-statistic for the logistic regression model was used to estimate PS score, which was 0.645 (95% CI: 0.595–0.696, P<0.001). This indicates moderate discrimination and suggests that the model was well calibrated (P=0.944, Hosmer-Lemeshow test). Table 2 lists the results of PS matching. Among patients who transferred indirectly, 92.4% (n=145) were matched to similar patients who transferred directly. ASD of all covariates in the matched cohort was ≤10%, and the covariate balance was improved.

Figure 4.

Cumulative incidences of (A) cardiac death and (B) all-cause death were significantly higher in indirect transfer patients than in direct transfer patients.

Figure 5.

Cumulative incidences of (A) cardiac death and (B) all-cause death according to Cox regression modeling were significantly higher in indirect transfer patients than in direct transfer patients. Variables with P<0.15 on univariate analysis were entered into multivariate analysis. CI, confidence interval; OR, odds ratio; PAD, peripheral artery disease.

Figure 6.

Cumulative incidences of (A) cardiac death and (B) all-cause death in propensity score-matched analysis tended to be higher in indirect transfer patients than in direct transfer patients.

Table 2. Baseline Propensity Score-Matched Data

	Indirect transfer	Direct transfer	P-value†
n=290	145 (50)	145 (50)
Age (years)	71±11	71±12	0.76
Male	100 (69)	101 (70)	0.9
Prior MI	8 (6)	7 (5)	0.79
HT	67 (46)	62 (43)	0.56
DM	45 (31)	44 (30)	0.90
Smoking	49 (34)	54 (37)	0.54
Family history	16 (11)	13 (9)	0.56
CKD	57 (39)	58 (40)	0.90
Anterior MI	63 (44)	67 (46)	0.64
Left main disease	6 (4)	8 (6)	0.58
Multiple vessel disease	55 (38)	55 (38)	>0.99
Killip class III/IV	22 (15)	20 (14)	0.74

Data given as mean±SD or n (%). ^†t-test or chi-squared test. The matched baseline characteristics of indirect transfer patients were similar to those of direct transfer patients. Abbreviations as in Table 1.

Discussion

The present study provides novel insights into the prehospital management of patients with primary PCI-treated STEMI in Japan. Indirect transfer patients had longer onset-to-balloon time than direct transfer patients, despite the shorter door-to-balloon time. In addition, indirect transfer patients had higher peak cardiac enzyme levels. Previous studies reported that there was a direct relationship between peak cardiac enzyme, infarct size, and prognosis.^16,17 Indirect transfer was independently associated with cardiac and all-cause death in 2 different models adjusted for contextual factors. Indirect transfer patients had less satisfactory reperfusion flow than direct transfer patients, as determined using TIMI flow grade and blush score. As reported, prolonged ischemia leads to disruption of the microvascular bed and edema of distal capillary beds, which contribute to no-reflow phenomenon and low TIMI flow grade and Brash score.^18–20 Door-to-balloon time was shorter in indirect transfer patients than in direct transfer patients. We hypothesized that the patients referred from other hospitals would go straight to treatment in the emergency room at a PCI-capable hospital, thereby shortening door-to-balloon time. Older patients, female patients and individuals without a history of MI did not tend to visit PCI-capable centers. The factor that contributed the most was age, according to OR when PS were calculated. It is also possible that region may partially explain this.

The early occurrence of reperfusion in STEMI patients is critical to improve prognosis, and any delay in door-to-balloon time results in worse recovery.^21,22 In a recent large study performed in Denmark, the time from first contact with the health-care system to the initiation of reperfusion, called system delay (Figure 1), was associated with mortality in primary PCI-treated STEMI patients.⁵ Another study in Canada analyzed transport systems and showed that direct transfer shortened both onset-to-balloon time and the time from arrival at the first hospital to the first balloon inflation.²³ These previous studies also investigated the effect on prognosis and concluded that the design of a STEMI citywide system permitting emergency medical services to bypass the nearest non-PCI-capable hospital and directly transport patients to PCI-capable centers was associated with a significant reduction in mortality.^9,23 Longer transfer time was also associated with a higher rate of poor outcome in patients undergoing interhospital transfer for primary PCI.⁸ The present study analyzed the details of how the transfer pathway to the hospital affects the outcome of primary PCI-treated STEMI patients. In particular, the present study population more closely represents real world Japanese clinical practice, including self-walk-in patients (18%). In contrast, the previous studies analyzed only patients who used the emergency care system. In addition, some of the present patients preferred to go to the family physician rather than a general hospital.

Recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend that every minute counts and that the time to treatment should be “as short as possible”. Direct emergency medical service transport to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI, and the ideal first medical contact-to-balloon time is ≤90 min. In addition, immediate transfer to a PCI-capable hospital for primary PCI is the recommended triage strategy for patients with STEMI who initially arrive at or are transported to a non-PCI-capable hospital, with a first medical contact-to-device time of ≤120 min. As such, effort is required to reduce door-in-door-out time, which describes the time delay between arrival to and transfer from a non-PCI-capable hospital.^6,7 In addition, use of prehospital 12-lead ECG likely contributes to an increased rate of direct transfer.²⁴

Although door-to-balloon time is a well-known predictor of mortality, onset-to-balloon time has not been assessed in many previous studies because of various methodological factors.^5,25–33 For example, patients find it difficult to remember the exact time of onset, and it is easy for the time to be altered or misremembered due to the distress caused by infarction. A confounding and selection bias known as the survivor-cohort effect also plays a role.³⁴ Patients in high-risk groups tend to present early, whereas those who present late have already survived the early stages, which include the highest risk of death.³⁵ Most previous relevant studies have been performed in Western countries at experienced PCI centers, although there have also been some registries in Japan.^36,37 Primary PCI is currently the main strategy for treating STEMI, and a large number of hospitals can perform PCI in Japan, but whether all centers achieve rapid primary PCI, however, remains unclear.^11–14 In a Japanese study performed in an urban setting, only a tertiary emergency center that was well organized with a 24-h on-site attending cardiologist achieved rapid primary PCI within the goal of door-to-balloon time <90 min.³⁸ Another study showed that the benefit of short door-to-balloon time was limited to individuals who presented early, which was dependent on prehospital delay. Onset-to-balloon time <3 h was associated with a lower incidence of poor outcome.³⁹

Study Limitations

This study has some limitations. First, it was not a prospective or randomized trial. Therefore, some already known or unknown confounding factors may have influenced the data. Most previous studies assessing the transfer of primary PCI patients, however, were also not randomized trials. Second, the patient population was restricted, and consisted only of patients who underwent primary PCI at a single center. In addition, we evaluated the relationship between facility preferences and outcomes in a specific region. There was also no information regarding medication. Glycoprotein IIb/IIIa inhibitors are not used in Japanese health care, although they were the standard therapy in previous Western studies assessing AMI. Finally, mean subject age was high, which limits the age-related information that can be extracted from the data.

Conclusions

Patients who visited regional emergency departments of PCI centers via an indirect route had longer onset-to-balloon time and worse prognosis than those who visited the centers directly. The present results suggest that regions should develop systems to transfer patients with STEMI to appropriate centers that are equipped to perform primary PCI. Not only hospital performance but also prehospital systems should be improved, including regional health-care systems, to achieve reperfusion therapy promptly in AMI patients.

Acknowledgment

Language assistance was provided by Crimson Interactive.

Supplementary Files

Supplementary File 1

Table S1. Direct-transfer patient characteristics

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-14-0678

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