Background

Primary percutaneous coronary intervention (PCI) is the preferred method to achieve reperfusion in patients with ST-segment elevation myocardial infarction (STEMI), provided that it can be performed in a timely fashion [1,2]. However, approximately 20%−50% of STEMI patients require transfer to a PCI center after initial presentation to a non-PCI capable hospital [3–6], resulting in longer ischemic times compared with direct admission to tertiary interventional hospitals. As a result, more than 40% of transferred patients in the United States fail to achieve the guideline-recommended first medical contact (FMC)-to-device time of 120 min [7], which may reduce myocardial salvage. In some studies, inter-hospital transfer for primary PCI has been identified as a major predictor of higher 12-month mortality [4], whereas other studies have not demonstrated clearly worsened outcomes after transfer for primary PCI [6,8–11].

Prolonged ischemic time has been associated with increased fibrin content of intracoronary thrombi [12], making them more resistant to anticoagulation with heparin which binds primarily with fluid-phase but not clot-bound thrombus. Bivalirudin, in contrast, has high affinity for both clot-bound and fluid-phase thrombin, preventing the initiation and propagation of clot formation [13]. Bivalirudin might thus be a more appropriate anticoagulation strategy for patients presenting late after symptom onset, including those undergoing inter-hospital transfer. In the HORIZONS-AMI trial, procedural anticoagulation with bivalirudin resulted in lower rates of cardiac mortality and major bleeding compared with heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), regardless of transfer for primary PCI [6]. However, in current clinical practice in which GPI are not routinely used with heparin and a post-PCI bivalirudin infusion is recommended after primary PCI, little is known regarding the outcomes of and the optimal anticoagulation strategy for transferred patients with STEMI.

In the large-scale BRIGHT-4 trial, bivalirudin plus a post-PCI high-dose infusion (1.75 mg/kg/h) for 2–4 hrs reduced the 30-day rates of all-cause mortality, major bleeding and stent thrombosis compared with heparin monotherapy in patients with STEMI undergoing primary PCI [14]. The present post hoc analysis therefore aimed to compare the clinical outcomes of patients with STEMI transferred to tertiary hospitals for PCI with those who presented directly at an interventional facility, and to investigate whether inter-hospital transfer had an impact on the outcomes of anticoagulation with bivalirudin versus heparin as used in contemporary clinical practice.

Methods

Results

Baseline characteristics

Among the 5,938 study patients, 2,121 (35.7%) were transferred to the tertiary hospital for primary PCI while 3,817 (64.3%) patients were directly admitted to a PCI-capable facility. The flowchart of the study is provided in Fig 1. Patients in the inter-hospital transfer group were less likely to have hypertension and history of MI or PCI compared with those in the direct admission group but were more likely to smoke and have anemia (Table 1). Symptom onset-to-FMC time was significantly shorter in the inter-hospital transfer group as was the duration from tertiary hospital arrival to wire time. However, after accounting for a median inter-hospital transfer time of 132 min, the median symptom onset-to-wire time was approximately 2 hrs longer in the inter-hospital transfer group compared with the direct admission group (6.00 versus 3.93 hrs, P < 0.0001) (Table 1 and Fig 2).

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Table 1. Baseline characteristics.

https://doi.org/10.1371/journal.pmed.1004679.t001

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Fig 1. The flowchart of the study population.

PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

https://doi.org/10.1371/journal.pmed.1004679.g001

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Fig 2. Intervals for patients to a PCI facility.

PCI, percutaneous coronary intervention; FMC, first medical contact.

https://doi.org/10.1371/journal.pmed.1004679.g002

Procedural data and medications are presented in Tables 2 and S1. Compared with the direct admission group, the patients requiring inter-hospital transfer were more likely to be treated with clopidogrel than ticagrelor, had a slightly higher use of radial artery access, were slightly less likely to undergo PCI (but more often in the left anterior descending than the right coronary artery), were less likely to undergo thrombus aspiration, and had better pre-PCI rates of TIMI 2/3 flow but similar post-PCI rates of TIMI 3 flow.

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Table 2. Medications and procedural data.

https://doi.org/10.1371/journal.pmed.1004679.t002

As presented in S2 and S3 Tables, baseline characteristics, procedural data, and medications among patients randomized to heparin versus bivalirudin in the inter-hospital transfer and direct admission groups were well-matched.

Clinical outcomes

At 30 days, there were no significant differences in the rates of the primary composite outcome, all-cause mortality, BARC types 3–5 bleeding, stent thrombosis, MACCE or NACE between the inter-hospital transfer and direct admission groups. However, acquired thrombocytopenia was slightly more common in the inter-hospital transfer group. These findings were similar after adjustment for differences in baseline characteristics, procedural data, and medications (Table 3).

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Table 3. Clinical outcomes at 30 days.

https://doi.org/10.1371/journal.pmed.1004679.t003

The outcomes of bivalirudin plus a post-PCI high-dose infusion for 2–4 hrs versus heparin monotherapy on 30-day clinical outcomes in the inter-hospital transfer and direct admission groups, adjusted for differences in baseline covariates and treatments, are shown in Table 4. There were no significant interactions between randomized anticoagulation use and the transfer versus direct admission subgroup on any of the 30-day primary or secondary endpoints (Fig 3).

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Table 4. Clinical outcomes at 30 days according to randomization to bivalirudin vs. heparin.

https://doi.org/10.1371/journal.pmed.1004679.t004

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Fig 3. Time-to-event curves at 30 days for the primary outcome and its components.

(A) All-cause death or BARC types 3–5 bleeding; (B) All-cause death; (C) BARC types 3–5 bleeding. BARC, Bleeding Academic Research Consortium.

https://doi.org/10.1371/journal.pmed.1004679.g003

As shown in S4 Table, the results from both standard Cox models and Cox frailty models for the primary outcome were consistent, which suggested that the observed associations were not significantly influenced by inter-center variability. Furthermore, we conducted a PSM analysis, which identified 1882 well-balanced pairs. The results of this sensitivity analysis (see S5 Table) were in line with our primary findings. Lastly, we performed an additional analysis excluding patients with symptom onset-to-wire time exceeding 24 hrs, and applied multivariable Cox models. The results (see S6 and S7 Tables) remained consistent with those from the primary analysis.

Discussion

In the present analysis from the BRIGHT-4 trial, 30-day clinical outcomes were not significantly worse in patients with STEMI presenting at a non-PCI capable hospital who were transferred to a tertiary facility for primary PCI compared with direct admission at the interventional center, despite an increase in total ischemic time of approximately 2 hrs. In addition, the relative effects of bivalirudin with a post-PCI high-dose infusion for 2–4 hrs compared with heparin monotherapy, with GPI use reserved for bail-out complications in both arms, were consistent for all 30-day primary and secondary outcomes in the inter-hospital transfer and direct admission groups. The principal results from the BRIGHT-4 trial that bivalirudin reduced the 30-day composite outcome of all-cause death or major bleeding thus apply to patients both presenting at a PCI capable center or requiring transfer, despite the additional delay required.

Although transferring STEMI patients to a tertiary hospital for primary PCI prolongs the total ischemic time, previous studies evaluating the effect of inter-hospital transfer versus direct admission on mortality in patients with STEMI undergoing primary PCI have yielded conflicting results [3–6,8–11,16–19]. For example, Chan and colleagues reported from a single-center prospective registry study of 594 STEMI patients that inter-hospital transfer compared with direct admission to the PCI center was associated with a longer total median ischemic time of 78 min, as well as higher 30-day and 1-year mortality [16]. Conversely, in the randomized HORIZONS-AMI trial of 3,602 patients with STEMI, 30-day and 1-year clinical outcomes were comparable in patients transferred for primary PCI compared with those directly admitted to a tertiary center, despite a reperfusion delay of approximately 67 min [6]. However, in neither of these studies was primary PCI performed with the regimens that are most widely recommended and used in contemporary practice, namely heparin monotherapy and bivalirudin with a several hour post-PCI high-dose infusion. These were the randomized anticoagulation regimens used in the large-scale BRIGHT-4 trial. Moreover, in BRIGHT-4 primary PCI was also routinely performed with radial artery access, and with use of ticagrelor in the majority of patients, practices that have been shown to further reduce mortality [20,21]. These considerations warranted a re-examination of the outcomes of STEMI patients presenting at non-PCI capable versus tertiary facilities in BRIGHT-4.

In BRIGHT-4, a substantial proportion (35.7%) of patients presenting with STEMI required inter-hospital transfer prior to primary PCI. This process delayed reperfusion by about 2 hrs. Nonetheless, after adjustment for differences in baseline covariates and treatments, this delay was not associated with a significant increase in mortality, major bleeding, MACCE or NACE. There might be several explanations for this observation. First, the benefit of reperfusion therapy in reducing mortality is greatest within the first 1–3 hrs after symptom onset, most likely due to the time-dependence of myocardial salvage before transmural infarction is established. After that early period, the impact of reperfusion therapy on reducing mortality is substantially less, and thus time to reperfusion is less critical [22,23]. In our study, 30-day cardiovascular and all-cause mortality was increased in patients with symptom onset-to-wire time of ≥3 hrs compared with <3 hrs, despite similar rates of ischemic and bleeding events, likely reflecting the impact of delayed reperfusion on myocardial salvage. Symptom onset-to-wire time ≥3 hrs was associated with mortality in both the direct admission and inter-hospital transfer groups. Thus, it is likely that the total ischemic time before reperfusion, rather than the mode of transfer, had a greater effect on survival in STEMI. In this regard, the somewhat shorter symptom onset to FMC and tertiary hospital door-to-wire times in the inter-hospital transfer group compared with the direct admission group likely mitigated the impact of the time required for inter-hospital transfer. Second, we cannot exclude the role that differences in baseline features and ancillary treatments in the inter-hospital transfer and direct admission groups might have had on the results. In the PL-ACS registry [4], transferred patients had higher-risk baseline characteristics, which might have contributed to their greater mortality at 30 days. In BRIGHT-4, however, clinical outcomes were similar both before and after covariate adjustment. Additionally, it is also worth noting that ticagrelor, providing faster and greater P2Y12 receptor inhibition than clopidogrel, was more frequently chosen in patients directly admitted for primary PCI, which might be due to a worse baseline clinical profile in the direct admission group or lack of ticagrelor in some referring hospitals. These limitations at referring hospitals emphasize the necessity for optimized reperfusion strategies in scenarios when delays are inevitable. Current guidelines advocate the pharmaco-invasive strategy when FMC-to-wire time exceeds 120 min [2]. However, our study excluded patients who received thrombolytic therapy prior to PCI, which limited our ability to evaluate the pharmaco-invasive strategy. This critical evidence gap highlights the urgent need for future studies comparing clinical outcomes between STEMI patients undergoing direct primary PCI and those receiving pharmaco-invasive therapy following inter-hospital transfer.

Importantly, in BRIGHT-4 the mode of transfer neither potentiated nor attenuated the benefits observed with bivalirudin with a post-PCI high-dose infusion for 2–4 hrs compared with heparin monotherapy. After covariate adjustment for differences in patient characteristics (e.g., differences in baseline TIMI flow rates) and adjunctive treatments (e.g., ticagrelor versus clopidogrel use, which take time to work in STEMI [24,25]), the relative hazards for all primary and secondary ischemic and bleeding outcomes with these anticoagulation regimens were consistent in the inter-hospital transfer and direct admission groups. Thus, the principal results of BRIGHT-4 apply to transfer patients as well as those presenting to a tertiary facility – STEMI patients undergoing primary PCI who are anticoagulated with bivalirudin plus a post-PCI high-dose infusion for 2–4 hrs have lower rates of all-cause mortality, major bleeding, stent thrombosis and NACE compared with heparin monotherapy [14]. Future studies with larger sample sizes or longer follow-up periods may help clarify whether this trend translates into a significant benefit.

The reduction in stent thrombosis in BRIGHT-4 after primary PCI with bivalirudin compared with heparin, even in patients presenting late after prolonged transfer, is notable. In the HORIZONS-AMI trial, the rate of stent thrombosis within the first 4 hrs after randomization was increased in patients treated with bivalirudin compared with heparin [26]. However, all heparin-treated patients in that trial also received a GPI, the only therapy shown to reduce stent thrombosis after stent implantation in STEMI [27], and bivalirudin was discontinued immediately after the PCI procedure, a risk factor for early stent thrombosis given its short (25-minute) half-life. In contrast, in BRIGHT-4, the platelet activation that is known to occur after heparin use alone [28] likely resulted in increased rates of early stent thrombosis in patients randomized to heparin monotherapy without routine GPI administration, and in the bivalirudin arm, the median 3-hr post-PCI bivalirudin infusion was sufficient to suppress stent thrombosis in the early risk period, as first described in the EUROMAX trial [29].

Symptom onset-to-FMC time in BRIGHT-4 was longer than in previous studies, in part due to inclusion of patients with STEMI as late as 48 hrs after symptom onset, as opposed to 12 or 24 hrs in previous studies [3,4,6,17]. Moreover, the inter-hospital transfer group had a median FMC-to-wire time of 3.57 hrs (reflecting large inter-hospital distances in China, as well as other logistical considerations in transport), well past the guideline-recommended duration of 120 min [2]. As door-in door-out (DIDO) times of ≤30 min have been associated with lower in-hospital mortality [30], it is imperative to minimize referral-related delays. However, tertiary hospitals managed to significantly reduce door-to-wire times in transferred patients by proactively preparing the catheterization laboratory and bypassing the emergency room [6].

This study highlighted the value of a time-based stratified management strategy that prioritized total ischemic time over the specific mode of transfer. It underscored the essential role of timely reperfusion in optimizing outcomes for both directly admitted and transferred STEMI patients. The results supported the hypothesis that bivalirudin might serve as a preferable anticoagulant option during primary PCI, offering enhanced safety and survival benefits compared to heparin monotherapy, regardless of whether patients were transferred or not. Nonetheless, further research is warranted to evaluate the long-term prognostic implications of inter-hospital transfer and to assess the sustained benefits of bivalirudin therapy over time.

This study also has some limitations. First, as a post hoc analysis, randomization was not stratified by transfer status, and no adjustment was made for multiple comparisons, which may have increased the risk of type I error. Although multivariable analysis was used to adjust for differences in baseline characteristics, medications and procedures (most of which were modest) between the inter-hospital transfer and direct admission groups, selection bias and unmeasured confounders cannot be excluded. These results should be interpreted with caution in the context of an underpowered subgroup analysis. Accordingly, our results should be considered hypothesis-generating rather than conclusive inference and warrant dedicated, prospective confirmation. Second, we did not collect detailed data regarding the use of emergency medical services and DIDO times, resulting in our inability to accurately analyze all the reasons for treatment delay. Finally, as the present analysis reports only 30-day outcomes, further studies are needed to investigate the impact of transfer on the long-term prognosis of STEMI patients.

We concluded that in the BRIGHT-4 trial, transferring patients with STEMI presenting at a non-PCI capable hospital to a tertiary facility for primary PCI was not associated with significantly worse 30-day mortality, MACCE or NACE compared with direct admission, despite treatment delays and longer times to reperfusion. Procedural anticoagulation with a post-PCI high-dose bivalirudin infusion for 2–4 hrs was associated with lower rates of 30-day all-cause mortality, major bleeding, and stent thrombosis compared with heparin monotherapy, regardless of whether patients were transferred or admitted directly to the interventional facility for primary PCI.

Supporting information

Acknowledgments

The authors appreciate the dedicated efforts of all of the clinical research collaborators in the BRIGHT-4 trial organization.