Abstract
Background
Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy compared with onsite fibrinolytic therapy (O‐FT) for ST‐segment–elevation myocardial infarction when delivered promptly. However, the contemporaneous data to inform the comparative benefits of primary PCI versus O‐FT, especially in developing countries, have been largely understudied.
Methods
We used data from the National Chest Pain Center Program (NCPCP), the largest nationwide registry in China, including patients with ST‐segment–elevation myocardial infarction treated with primary PCI or O‐FT from January 2016 to December 2022. Patients were matched using propensity scores, and the PCI‐related delay was defined as the difference between the observed door‐to‐wiring time and the door‐to‐needle time. Mortality outcomes were assessed at different delay intervals (<60 minutes, 60–90 minutes, >90 minutes). Subgroup analyses were conducted based on age, infarction location, and Killip classification.
Results
In 19 334 matched patients, primary PCI demonstrated a significant mortality benefit over O‐FT when PCI‐related delays were <60 minutes (2.34% versus 6.01%). However, this advantage diminished when delays exceeded 90 minutes. The critical threshold at which PCI lost its mortality benefit was identified as 119.51 minutes (door‐to‐wiring time – door‐to‐needle time). Subgroup analyses showed that older patients, patients with anterior infarction, and those with a higher Killip class appeared to have lower equipoise thresholds.
Conclusions
Primary PCI offers a mortality benefit compared with O‐FT in patients with timely treated ST‐segment–elevation myocardial infarction, but treatment delays can mitigate this benefit. In settings with prolonged treatment delays, immediate fibrinolysis may be a more effective strategy. Treatment decisions should incorporate both patient characteristics and health care system constraints to optimize ST‐segment–elevation myocardial infarction outcomes.
Keywords: comparative research, fibrinolysis, myocardial infarction, percutaneous coronary intervention, transfer
Subject Categories: Quality and Outcomes, Clinical Studies
Nonstandard Abbreviations and Acronyms
- ASD
absolute standardized difference
- CAPTIM
Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction
- CCA
Chinese Cardiovascular Association
- DN
door‐to‐needle
- DW
door‐to‐wiring
- FT
fibrinolytic therapy
- FTT
Fibrinolytic Therapy Trialists'
- NCPCP
National Chest Pain Center Program
- O‐FT
onsite fibrinolytic therapy
- PPCI
primary percutaneous coronary intervention
- STREAM
Strategic Reperfusion Early After Myocardial Infarction
Clinical Perspective.
What Is New?
This study uses national real‐world data from China to quantify the relative delay threshold (119 minutes) beyond which the mortality benefit of primary percutaneous coronary intervention compared with onsite fibrinolysis is no longer observed in patients with ST‐segment–elevation myocardial infarction.
Patients who were older, had higher Killip class, or presented with inferior infarction appeared to have lower equipoise thresholds.
What Are the Clinical Implications?
In settings with prolonged transfer delays—particularly in low‐resource or rural regions—timely onsite fibrinolysis may be a reasonable alternative to primary percutaneous coronary intervention.
Our findings support the 120‐minute threshold recommended in current guidelines and provide empirical validation from a large‐scale Chinese population with ST‐segment–elevation myocardial infarction.
Reperfusion strategies should be tailored not only by treatment availability but also by real‐time assessment of system delays and patient‐specific risk factors.
The primary goal of reperfusion therapy for ST‐segment–elevation myocardial infarction (STEMI) is to rapidly restore blood flow in the infarct‐related artery in order to minimize myocardial damage and improve patient outcomes. 1 Primary percutaneous coronary intervention (PPCI) is widely regarded as the preferred treatment option in comparison to onsite fibrinolytic therapy (O‐FT) for patients with STEMI, particularly when it can be performed in a timely manner. 2 Previous studies in developed countries have shown that PPCI significantly improves both survival rates and quality of life for patients with STEMI. 3 , 4 However, the comparative effectiveness of PPCI versus O‐FT in developing countries has not been thoroughly studied. It is worth noting that health care resource distribution in China and other developing countries is uneven, with significant disparities between regions and restricted access to health care resources, 5 which might produce different outcomes compared with high‐income countries. Similar to other developing countries, nearly half of secondary and tertiary hospitals lack the capacity to perform timely PCI in China, which results in many patients with STEMI requiring interhospital transfer to facilities capable of performing PPCI. 6 These transfers inevitably lead to delays in reperfusion therapy compared with administration of O‐FT.
Transfer delays can directly affect treatment outcomes, as shown by the time‐myocardial necrosis curve in patients with acute myocardial infarction, where the rate of heart muscle damage increases rapidly in the early stages. 7 Previous studies have demonstrated that while PPCI offers a significant mortality benefit compared with O‐FT, this advantage is mitigated as treatment delays increase. 8 , 9 A PCI‐related delay potentially mitigating the benefits of PCI has been calculated in the range of 110 to 120 minutes. 2 However, previous data are from older studies and registries, and patients undergoing fibrinolysis did not undergo routine early angiography. 2 The 2023 European Society of Cardiology guidelines highlight the lack of current data to establish the treatment delay threshold at which PCI loses its advantage compared with fibrinolysis. With recent improvements in both PCI and fibrinolytic therapies, striking a balance between the delays caused by interhospital transfers and the immediate availability of FT has become a critical consideration in clinical decision‐making. Prior studies were either from high‐income countries or had a relatively small sample size, limiting the generalizability of the findings. While the guidelines have been established in high‐income countries, their applicability to developing countries has been underexplored. In addition, it remains to be determined which populations are particularly likely to benefit from PPCI or O‐FT therapy.
To fill these research gaps, we conducted a nationwide cohort study between 2016 and 2022 based on data from the National Chest Pain Center Program (NCPCP), a continuous quality improvement initiative designed to monitor and enhance health care for patients with acute coronary syndromes. 10 This program included the largest number of patients undergoing PPCI or O‐FT in China and provides a valuable opportunity to assess the impact of reperfusion delays on the comparative efficacy of PPCI and O‐FT in a large national cohort. In the present study, we compared the benefits of PPCI and O‐FT at various treatment delay intervals to determine the optimal reperfusion strategy for patients with STEMI, and investigated whether the point at which PPCI loses its advantage compared with O‐FT varies based on patient factors, such as age, disease severity, and the location of the myocardial infarction. Our study aimed to shift the focus from merely following guidelines to adapting them to local resources and constraints.
METHODS
Data Sharing
Please contact the corresponding author for more information.
Ethics approval and consent to participate
Ethical approvals from the NCPCP were obtained from the institutional review boards of the GuSu group ethics committee (GUSU19005). Informed consent was obtained from registered hospitals for research approval to collect data in the NCPCP without requiring patient informed consent.
Data were obtained from the Chinese Cardiovascular Association (CCA) Database‐Chest Pain Center of NCPCP, an ongoing, national data set for voluntary quality improvement maintained by the CCA. The data that support the findings of this study are available from the corresponding author on reasonable request. Hospitals participating in the NCPCP submitted data on patients with STEMI via a centralized web‐based system. The design and implementation of the NCPCP have been described in detail elsewhere. 10 Ethical approval was granted by the GuSu Group Ethics Committee (GUSU19005), with institutional review boards overseeing the NCPCP. Informed consent for data collection was obtained from participating hospitals, allowing the research to proceed without the need for individual patient consent. We strictly followed the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines, ensuring that our study sets a benchmark for excellence in observational research.
Study Population
We included patients with STEMI (<12 hours after the onset of pain) who were treated with either PPCI or O‐FT between January 2016 and December 2022. Patients with STEMI were identified using discharge diagnosis codes from the International Classification of Diseases, Tenth Revision (ICD‐10). Patients were excluded if they: (1) had missing data for door‐to‐wiring (DW) or door‐to‐needle (DN) time; (2) had a time >12 hours since the onset of pain; (3) had negative DW or DN time; (4) had DW or DN time >6 hours, since patients with time >6 hours were not considered to have been treated with primary reperfusion therapy; and (5) had missing data for propensity score covariates (Figure 1). In the case of patients with multiple admissions, the focus was on the initial admission. The final selection of eligible patients yielded a total of 168 341 unmatched cases, comprising 155 695 patients who underwent PCI and 12 646 who received FT.
Figure 1. Flowchart of the study.
CCA indicates Chinese Cardiovascular Association; DN, door‐to‐needle; DW, door‐to‐wiring; O‐FT, onsite fibrinolytic therapy; PCI, percutaneous coronary intervention; and STEMI, ST‐segment–elevation myocardial infarction.
Covariate Characteristics
To ensure the integrity of the data, any covariates included in this study were required to have a maximum of 25% missing data in the original data set. The study encompassed a range of patient demographic characteristics, as well as data pertaining to the onset reactions, clinical characteristics, and hospital‐level characteristics. The demographic characteristics included age, sex, and medical history risk factors. The medical history of the patients included a history of hypertension, diabetes, smoking, and coronary heart disease. The onset reaction covariates included levels of chest pain (persistent chest pain was the first level) and breath, pulse, and heart rates. The clinical covariates included the Killip class and infarction location. The hospital‐level characteristics included geographic location (eastern, western, or middle based on the province geographic distribution in China) and the mode of arrival (including the method of emergency medical services activation, hospital transfer, and self‐arrival).
Definition of Calculating the PCI‐Related Delay Time
The primary outcomes were the PCI‐related delay time (DW time–DN time) for matched data, which was evaluated to ascertain the impact of reperfusion delays on the comparative efficacy of PCI and FT. The hypothesis was set as follows: an increase in DW–DN time would result in a reduction in the advantage of PCI compared with FT. In the case of patients undergoing PPCI, the DW time was calculated as the difference between the time of arrival at the first hospital and the wire time at the hospital with PCI capabilities. The DN time was calculated by subtracting the FT initiation time from the time of arrival at the hospital. The PCI‐related delay time for matched data was calculated by subtracting the DN time from the DW time, which represented the time delay in implementing PCI over FT. 11
Statistical Analysis
Descriptive statistics were conducted for the entire cohort, which was stratified by predefined therapy subgroups. These subgroups were defined as: (1) patients treated with primary PCI, and (2) patients treated with O‐FT. The characteristics of both unmatched and matched patients were described and compared separately. Absolute standardized differences (ASDs) were employed to facilitate a comparative analysis of the various characteristics between patients with PCI and patients with FT. 12 , 13 This approach was selected due to the considerable sample size, with an ASD exceeding 10% representing a practical significant difference in variables between the 2 therapy subgroups.
Match Processing
We employed propensity score matching to adjust for variations in initial risk factors and baseline characteristics between patients who underwent PCI and those underwent FT. The score was calculated using a broad, noninteractive multivariable logistic regression model, which represents the conditional probability of a patient being included in the PCI group based on the included covariates. Subsequently, patients who underwent PPCI were matched with those who underwent FT, using the logit‐transformed propensity score with a caliper limit of 0.03. This resulted in each patient being matched 1:1 with replacement. Patients who underwent either PCI or FT and who could not be adequately matched were excluded from the study population. The final matched study population comprised 9667 patients who underwent PPCI and 9667 patients who underwent FT (Figure 1).
Primary Analysis
The time distributions are described overall and at 3 levels of PCI‐related delay time (<60 minutes, 60–90 minutes, >90 minutes), and the differences in death rates between patients treated with PCI and patients treated with FT at each level of PCI‐related delay time are also presented. In addition, we divided the matched patients into tertiles based on PCI‐related delay time. To account for the in‐hospital outcome (death), a conditional logistic regression was performed to determine the risk factors that influenced the patient's outcome. To ensure the robustness of the results against multiple comparisons, we applied Benjamini‐Hochberg correction, which is a statistical method used to control the false discovery rate in multiple hypothesis testing. 14 Based on the coefficient and SD for each variable, we also calculated the E‐value for each association. The E‐value quantifies the minimum strength that an unobserved confounder would need to have in order to fully explain the observed association. As such, it provides a metric through which the potential impact of unobserved confounding on the findings can be assessed. 15
To evaluate the comparative benefits of PPCI versus O‐FT treatments, we conducted a modeling analysis to assess the PCI‐related advantage (the outcome difference between patients treated with PCI and those treated with FT). This was achieved by conditional logistic regression, which accounted for the paired structure of the data set. The objective of this approach was to gain insight into the impact of different reperfusion methods and treatment delays on patient outcomes. Separate models were developed for each treatment group (PCI and FT) to describe the clinical outcome (death), adjusting for variables such as demographic characteristics, onset reactions, clinical and hospital‐level factors, and the timing of treatment (recorded as DW or DN in minutes), with a specific variable indicating treatment assignment (FT). To identify the threshold at which the time delay (DW–DN) negated the advantage of PCI, termed the equipoise time, we set the difference between the model equations for the PCI and FT groups to zero and then solved for the time point at which the outcome differences were equal, thus identifying the point at which the advantage of PCI was nullified. To ensure consistency, the same covariates used in the initial propensity score calculations were included in these analytical models. Furthermore, to more accurately identify potential nonlinear (curvilinear) relationships between the DW–DN time and patient outcomes, we incorporated a term for the DW–DN variable into the models. We also conducted subgroup analyses to investigate whether the equipoise time differed between patient groups, including those younger and those older than 70 years, different Killip classifications (Killip I to III versus Killip IV), and infarction location (anterior versus inferior).
Sensitivity Analysis
We conducted a sensitivity analysis to account for potential variations in determining the equipoise time point, defined as the time at which the outcome differences became zero, nullifying the advantage of PCI. This analysis was conducted in accordance with specific conditions, with a particular focus on patients who were taking a third‐generation fibrinolytic agent (fibrin‐specific agent tenecteplase or reteplase). To achieve this, we repeated the matching process, reestablished the model equations, and adjusted the variables used in the primary analysis steps. This enabled the calculation of the various equipoise time points at which the advantage of PCI was negated.
All data cleaning and preprocessing were conducted using the R software, version 4.3.2. All analyses in this study were conducted using the R software version 4.3.2 (R Foundation for Statistical Computing).
RESULTS
Characteristics for the matched and unmatched patients with TEMI who underwent PPCI or FT therapy are shown in Table 1. In the matched population, ≈75% of patients were men in each treatment group, ≈50% of patients had a medical history of hypertension, and ≈79% of patients had persistent chest pain at the onset of symptoms. Approximately 65% of patients who underwent PCI and 66% who received FT arrived at the hospital by themselves. The ASD between the matched groups was ≤3% for all covariates. Table 2 presents the time distributions for the overall matched and unmatched patients, as well as for the 3 time levels (<60 minutes, 60–90 minutes, and >90 minutes). The number of patients in each treatment group with PCI‐related delays of <60 minutes, 60 to 90 minutes, and >90 minutes were 1233, 1605, and 6829, respectively. The median DW time was 152 minutes (interquartile range [IQR], 112–201 minutes) among matched patients, and median DN time was 31 minutes (IQR, 21–49 minutes). The median PCI‐related delay time was 115 minutes (IQR, 72–171 minutes) in the overall matched patients, 36 minutes (IQR, 13–52 minutes) in patients with delays of <60 minutes, 75 minutes (IQR, 65–81 minutes) in patients with delays of 60 to 90 minutes, and 147 minutes (IQR, 103–196 minutes) in patients with delays of >90 minutes.
Table 1.
Characteristics of the Patients With STEMI and by Therapy Types
| No. (%) of patients | ||||||
|---|---|---|---|---|---|---|
| Patients before matching | Matched patients | |||||
| PPCI | O‐FT | ASD* | PPCI | O‐FT | ASD* | |
| (N=155 695) | (N=12 646) | (N=9667) | (N=9667) | |||
| Age, y | 14.96 | 2.71 | ||||
| Median (IQR) | 62 (55–71) | 64 (56–73) | 62 (55–70) | 62 (54–71) | ||
| Mean ±SD | 61.73±12.96 | 63.68±13.11 | 61.94±12.92 | 62.29±12.87 | ||
| Age groups, y | ||||||
| 18 to ≤49 | 23 650 (15.19) | 1734 (13.71) | 4.21 | 1438 (14.88) | 1371 (14.18) | 1.99 |
| 50 to ≤59 | 42 007 (26.98) | 2924 (23.12) | 8.92 | 2619 (27.09) | 2537 (26.24) | 1.92 |
| 60 to ≤69 | 40 278 (25.87) | 3332 (26.35) | 1.09 | 2511 (25.97) | 2545 (26.33) | 0.82 |
| 70 to ≤79 | 35 358 (22.71) | 3428 (27.11) | 10.19 | 2224 (23.01) | 2312 (23.92) | 2.15 |
| ≥80 | 14 402 (9.25) | 1228 (9.71) | 1.57 | 875 (9.05) | 902 (9.33) | 0.97 |
| Sex | 5.44 | 0.07 | ||||
| Male | 115 697 (74.31) | 9693 (76.65) | 7259 (75.09) | 7262 (75.12) | ||
| Female | 39 998 (25.69) | 2953 (23.35) | 2408 (24.91) | 2405 (24.88) | ||
| Hypertension | 79 233 (50.89) | 6009 (47.52) | 6.74 | 4839 (50.06) | 4740 (49.03) | 2.06 |
| Diabetes | 34 860 (22.39) | 2627 (20.77) | 3.94 | 2096 (21.68) | 2054 (21.25) | 1.05 |
| Smoking | 65 345 (41.97) | 4680 (37.01) | 10.16 | 3978 (41.15) | 3844 (39.76) | 2.83 |
| CHD | 66 186 (42.51) | 5176 (40.93) | 3.20 | 4019 (41.57) | 3986 (41.23) | 0.69 |
| Onset characteristics | ||||||
| Chest pain | ||||||
| Persistent | 124 852 (80.19) | 9974 (78.87) | 3.27 | 7689 (79.54) | 7683 (79.48) | 0.15 |
| Intermittent | 20 271 (13.02) | 1670 (13.21) | 0.56 | 1225 (12.67) | 1229 (12.71) | 0.12 |
| Alleviate | 10 572 (6.79) | 1002 (7.92) | 4.33 | 753 (7.79) | 755 (7.81) | 0.07 |
| Breath rate | 2.13 | 0.11 | ||||
| Normal | 150 261 (96.51) | 12 253 (96.89) | 9355 (96.77) | 9357 (96.79) | ||
| Abnormal† | 5434 (3.49) | 393 (3.11) | 312 (3.23) | 310 (3.21) | ||
| Pulse rate | 10.47 | 2.52 | ||||
| Normal | 117 176 (75.26) | 10 070 (79.63) | 7279 (75.30) | 7384 (76.38) | ||
| Abnormal† | 38 519 (24.74) | 2576 (20.37) | 2388 (24.70) | 2283 (23.62) | ||
| Heart rate | 6.75 | 2.47 | ||||
| Normal | 118 390 (76.04) | 9973 (78.86) | 7392 (76.47) | 7493 (77.51) | ||
| Abnormal† | 37 305 (23.96) | 2673 (21.14) | 2275 (23.53) | 2174 (22.49) | ||
| Killip class | ||||||
| 1 | 105 496 (67.76) | 8358 (66.09) | 3.55 | 6519 (67.44) | 6408 (66.29) | 2.44 |
| 2 | 19 898 (12.78) | 2103 (16.63) | 10.89 | 1361 (14.08) | 1435 (14.84) | 2.16 |
| 3 | 12 645 (8.12) | 1176 (9.30) | 4.19 | 856 (8.85) | 819 (8.47) | 1.35 |
| 4 | 17 656 (11.34) | 1009 (7.98) | 11.39 | 931 (9.63) | 1005 (10.40) | 2.57 |
| Region | ||||||
| Eastern | 51 286 (32.94) | 3927 (31.05) | 4.05 | 3053 (31.58) | 2999 (31.02) | 1.21 |
| Western | 51 987 (33.39) | 4322 (34.18) | 1.67 | 3274 (33.87) | 3318 (34.32) | 0.95 |
| Middle | 52 422 (33.67) | 4397 (34.77) | 2.32 | 3340 (34.55) | 3350 (34.65) | 0.21 |
| In hospital mode | ||||||
| Call EMS | 21 275 (13.66) | 2077 (16.42) | 7.73 | 1478 (15.29) | 1495 (15.46) | 0.47 |
| Hospital transfer | 51 441 (33.04) | 1820 (14.39) | 44.94 | 1902 (19.68) | 1789 (18.51) | 2.98 |
| Self‐arrival | 82 979 (53.30) | 8749 (69.18) | 33.05 | 6287 (65.04) | 6383 (66.03) | 2.09 |
| Infarction site | 2.18 | 0.87 | ||||
| Anterior | 74 889 (48.10) | 6221 (49.19) | 4706 (48.68) | 4748 (49.12) | ||
| Inferior | 80 806 (51.90) | 6425 (50.81) | 4961 (51.32) | 4919 (50.88) | ||
ASD indicates absolute standardized difference; CHD, coronary heart disease; EMS, emergency medical services; IQR, interquartile range; O‐FT, onsite fibrinolytic therapy; PPCI, primary percutaneous coronary intervention; and STEMI, ST‐segment–elevation myocardial infarction.
An absolute value of standardized difference 10%, represents a meaningful imbalance between comparison groups.
Abnormal refers to when the patient's breathing, pulse, and heart rates are outside the normal physiological range at the time of onset.
Table 2.
Time Intervals of Patients With STEMI and by PCI‐Related Delay Levels
| PCI‐rlated delay <60 min | PCI‐related delay 60–90 min | |||||
|---|---|---|---|---|---|---|
| PPCI | O‐FT | Total | PPCI | O‐FT | Total | |
| (n=1233) | (n=1233) | (N=2466) | (n=1605) | (n=1605) | (N=3210) | |
| Onset to first medical contact | ||||||
| Mean ±SD | 143.66±134.01 | 215.76±264.72 | 180.27±192.69 | 121.73±114.92 | 201.21±256.62 | 166.30±179.75 |
| Median (IQR) | 69 (45–102) | 103 (85–148) | 91 (65–137) | 76 (56–110) | 107 (83–143) | 87 (62–121) |
| DW* | ||||||
| Mean ±SD | 102.14±42.21 | N/A | N/A | 118.63±39.01 | N/A | N/A |
| Median (IQR) | 93 (76–115) | N/A | N/A | 108 (91–124) | N/A | N/A |
| DN | ||||||
| Mean ±SD | N/A | 78.16±58.31 | N/A | N/A | 39.66±31.03 | N/A |
| Median (IQR) | N/A | 64 (53–78) | N/A | N/A | 33 (23–50) | N/A |
| PCI‐related delay (DW–DN) | ||||||
| Mean ±SD | 23.98±44.55 | 78.97±9.02 | ||||
| Median (IQR) | 36 (13–52) | 75 (65–81) | ||||
| Minutes | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| PCI‐related delay>90 mins | All matched | Unmatched | |||||||
| PPCI (N=6829) | O‐FT (N=6829) | Total (N=13 658) | PPCI (N=9667) | O‐FT (N=9667) | Total (N=19 334) | PPCI (N=155 695) | O‐FT (N=12 646) | Total (N=168 341) | |
| Onset to first medical contact | |||||||||
| Mean ±SD | 149.25±119.67 | 234±280.97 | 182.01±195.86 | 143.08±124.35 | 226.15±273.90 | 177.61±187.31 | 140.68±121.35 | 258.96±305.76 | 196.48 (249.75) |
| Median (IQR) | 127 (95–166) | 152 (107–194) | 136 (102–183) | 106 (78–154) | 129 (98–187) | 115 (88–167) | 105 (79–152) | 169 (118–207) | 155 (109–192) |
| DW* | |||||||||
| Mean ±SD | 195.65±67.27 | N/A | N/A | 169.66±69.94 | N/A | N/A | 165.91±67.25 | N/A | N/A |
| Median (IQR) | 183 (143–229) | N/A | N/A | 152 (112–201) | N/A | N/A | 149 (112–197) | N/A | N/A |
| DN | |||||||||
| Mean ±SD | N/A | 33.33±21.79 | N/A | N/A | 41.89±34.06 | N/A | N/A | 44.97±38.73 | N/A |
| Median (IQR) | N/A | 29 (19–41) | N/A | N/A | 31 (21–49) | N/A | N/A | 34 (23–52) | N/A |
| PCI‐related delay (DW–DN) | |||||||||
| Mean ±SD | 162.32±61.68 | 127.77±74.87 | |||||||
| Median (IQR) | 147 (103–196) | 115 (72–171) | |||||||
DN indicates door‐to‐needle; DW, door‐to‐wiring; IQR, interquartile range; N/A, not available; O‐FT, onsite fibrinolytic therapy; PCI, percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; and STEMI, ST‐segment–elevation myocardial infarction.
The DW time was calculated as the difference between the time of arrival at the first hospital and the wire time at the hospital with PCI capabilities.
Table 3 presents the clinical mortality outcomes for the overall patients and for each level of PCI‐related delay time. Among the overall matched patients, the mortality rates were slightly higher in the FT group than in the PCI group (5.26% versus 4.12%, ASD=5.39%). An advantage for PCI was identified within a PCI‐related delay of <60 minutes (mortality rate, 2.34% versus 6.01%, ASD=18.43%), with such an advantage for PCI versus FT becoming less pronounced in a PCI‐related delay of 60 to 90 minutes (mortality rate, 3.06% versus 3.99%, ASD=5.04%). In the group with PCI‐related delays of >90 minutes, 13 658 of the 19 334 patients were included in the analysis. However, there was no significant imbalance in mortality rates between the 2 groups (4.89% versus 5.18%, ASD=1.33%). The analysis revealed that, based on the 3 PCI‐related delay tertiles, PCI only had a significant advantage versus FT in the first tertile. The median PCI‐related delay time in this tertile was 61 minutes (IQR, 38–76 minutes), and the mortality rate was 2.67% versus 5.31%, with an ASD of 13.52%. No meaningful mortality differences were identified between PCI and FT in the second and third tertiles. In the second tertile, the median PCI‐related delay time was 109 minutes (IQR, 98–125 minutes), with a mortality rate of 4.09% versus 5.28% (ASD=5.63%). In the third tertile, the median PCI‐related delay time was 197 minutes (IQR, 164–238 minutes), with a mortality rate of 5.35% versus 4.97% (ASD=1.72%).
Table 3.
In‐Hospital Outcomes of the Patients With STEMI and by PCI‐Related Delay Levels
| No. | DW–DN, median (IQR) | In‐hospital death | |||
|---|---|---|---|---|---|
| PPCI, % | O‐FT, % | ASD | |||
| Unmatched | 168 341 | 4.22 | 7.19 | 12.83 | |
| Matched | 19 334 | 115 (72–171) | 4.12 | 5.26 | 5.39 |
| DW*–DN <60 min | 2466 | 36 (13–52) | 2.34 | 6.01 | 18.43 |
| DW–DN 61–90 min | 3210 | 75 (65–81) | 3.06 | 3.99 | 5.04 |
| DW–DN >90 min | 13 658 | 147 (103–196) | 4.89 | 5.18 | 1.33 |
| DW–DN tertile 1 | 6399 | 61 (38–76) | 2.67 | 5.31 | 13.52 |
| DW–DN tertile 2 | 6477 | 109 (98–125) | 4.09 | 5.28 | 5.63 |
| DW–DN tertile 3 | 6458 | 197 (164–238) | 5.35 | 4.97 | 1.72 |
ASD indicates absolute standardized difference; DN, door‐to‐needle; DW, door‐to‐wiring; IQR, interquartile range; O‐FT, onsite fibrinolytic therapy; PCI, percutaneous coronary intervention; PPCI, primary percutaneous coronary intervention; and STEMI, ST‐segment–elevation myocardial infarction.
The DW time was calculated as the difference between the time of arrival at the first hospital and the wire time at the hospital with PCI capabilities.
Regarding the outcome variable of mortality, we identified the following risk factors as being associated with a higher mortality odds ratio (OR) (Figure 2). The results indicated that there was a statistically significant association between DW–DN 60 to 90 minutes and mortality (OR, 1.11 [95% CI, 1.07–1.15]), as well as between DW–DN >90 minutes and mortality (OR, 1.41 [95% CI, 1.28–1.55]). In addition, there was a statistically significant association between age 60 to 69 years and mortality (OR, 1.10 [95% CI, 1.04–1.16]), as well as between age ≥80 years and mortality (OR, 1.09 [95% CI, 1.06–1.13]). Abnormal pulse rate (OR, 1.03 [95% CI, 1.02–1.05]), Killip class III (OR, 1.21 [95% CI, 1.13–1.28]), Killip class IV (OR, 1.31 [95% CI, 1.16–1.47]), and western region (OR, 1.25 [95% CI, 1.12–1.38]) were also identified as risk factors. The following risk factors were found to be associated with a lower mortality OR: hospital transfer via the emergency department (OR, 0.51 [95% CI, 0.44–0.58]), self‐arrival (OR, 0.52 [95% CI, 0.47–0.57]), and lower arm infarction location (OR, 0.72 [95% CI, 0.67–0.78]).
Figure 2. Factors associated with in‐hospital mortality of patients with STEMI.
CHD indicates coronary heart disease; DN, door‐to‐needle; DW, door‐to‐wiring; and STEMI, ST‐segment–elevation myocardial infarction.
In patients with overall matching characteristics, the conditional logistic regression model revealed no statistically significant difference in mortality rates between PCI and FT with DW–DN times exceeding 119.51 minutes (Figure 3). A subgroup analysis was conducted to investigate potential differences in the response to the equipoise time point in specific conditions and variables. Following the reestablishment of model equations and the adjustment of variables for each subgroup, the time point at which PCI lost its mortality advantage exhibited slight alterations in the following subgroups: (1) Killip 1 to 3 class, 119.76 minutes; (2) Killip 4 class, 118.23 minutes; (3) aged <70 years, 120.17 minutes; (4) aged ≥70, 119.33 minutes; (5) anterior infarction, 118.41 minutes; (6) inferior infarction, 120.28 minutes; and (7) aged ≥70 years, anterior infarction and Killip class IV, 117.86 minutes (Figures S1 and S2).
Figure 3. Relationship between PCI‐related delay (minutes) and in‐hospital mortality.
A, Total matched patients. B, Patients treated with third‐generation fibrinolytic medications. DN indicates door‐to‐needle; DW, door‐to‐wiring; and PCI, percutaneous coronary intervention.
Sensitivity analysis demonstrated that, among the included patients with FT who were treated exclusively with the fibrin‐specific agents tenecteplase or reteplase (comprising 7308 patients treated with PCI and 7308 patients treated with FT), PCI no longer conferred a mortality benefit when the time exceeded 119.17 minutes (Figure 3).
DISCUSSION
Our study aimed to evaluate the comparative benefits of PPCI versus O‐FT for patients with STEMI at various reperfusion delay intervals, using data from the largest nationwide Chinese cohorts collected in a real‐world setting, emphasizing the impact of door‐to‐treatment time. While previous studies have established the threshold of 120 minutes for PCI, with delayed treatment diminishing its benefits, the specific application of these findings in developing countries, including China, has remained underexplored. Furthermore, our study revealed that >40% of patients with STEMI undergoing PPCI in China fail to achieve the expected benefits of O‐FT due to delays in PCI implementation (Figure S3). This emphasizes a considerable deficit in the timely provision of PCI, thereby reinforcing the need to optimize care pathways to reduce delays and maximize the benefits of PPCI in clinical practice.
Our findings suggest that, similar to high‐income countries, time‐to‐treatment significantly influences mortality outcomes, yet this effect may manifest differently due to contextual factors specific to developing country settings, including health care infrastructure and access to timely interventions. To illustrate, the STREAM (Strategic Reperfusion Early After Myocardial Infarction) trial demonstrated that early fibrinolysis in conjunction with contemporary antithrombotic therapy and timely coronary angiography can be an effective alternative when PPCI is delayed beyond 60 minutes. 16 A meta‐analysis by Dalby et al demonstrated that, despite transfer delays, PPCI reduces mortality, reinfarction, and stroke rates. However, when delays exceed a critical threshold, fibrinolysis becomes the preferred strategy. 17 In addition, the CAPTIM (Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction) study supported the use of prehospital fibrinolysis when timely PCI is not feasible, further reinforcing these findings. 18
The results of our study indicate that 119.51 minutes represents the critical time threshold beyond which the mortality benefit of PPCI compared with O‐FT is no longer evident. Although first medical contact–to‐device time is often recommended to capture total ischemic delay, in China, >75% of patients with ACS present directly to hospitals without using emergency medical services, and only a minority (<10%) arrive via ambulance. Thus, for most patients, the first medical contact occurs at the hospital door. This, along with the limited availability of standardized first medical contact data, led us to adopt DW time as a practical and consistent surrogate, in line with previous studies in similar settings. 11 These findings are in close alignment with those of Pinto et al, who posited that the benefits of PCI diminish after ≈121 minutes of delay. 11 These results are consistent with the current European Society of Cardiology guideline, which recommend FT when primary PCI cannot be performed within 120 minutes of first medical contact. 2 Moreover, our study extends these findings by identifying patient‐specific factors, such as age, Killip classification, and infarction location, which influence the optimal reperfusion strategy. For example, the subgroup analyses indicate that older patients and those with higher Killip classifications may derive greater benefit from immediate fibrinolysis when faced with prolonged transfer delays. Our study highlights that time‐to‐treatment is a crucial determinant of mortality even in China, with its vast geographical diversity, variable healthcare resources, and regional disparities, presenting a unique challenge in adhering to international treatment guidelines.
Subgroup analyses highlight the pivotal influence of patient‐specific factors in determining the optimal reperfusion strategy, with PPCI and O‐FT emerging as the most suitable options. For example, older patients, those with anterior wall infarctions, and patients with higher Killip classifications may derive greater benefit from immediate fibrinolysis when faced with prolonged transfer delays. The American College of Cardiology/American Heart Association STEMI guideline has recommended that both patient‐related risk factors, such as age and comorbidities, and hospital‐related factors, such as proximity to PCI‐capable centers, be taken into account when selecting a reperfusion strategy. 18 Our findings provide further support for this approach, reinforcing the importance of personalized treatment strategies that are tailored to the individual patient profile. These results emphasize the necessity for more detailed clinical guidelines that assist health care providers in making well‐informed, patient‐centered decisions while accounting for logistical challenges such as transfer times and hospital resource availability. 19 , 20 It is recommended that future policy give priority to formulating comprehensive guidelines that allow clinicians to achieve optimal treatment outcomes by weighing patient‐specific factors alongside real‐world challenges.
Our findings indicate that >40% of patients with STEMI undergoing PPCI in China do not achieve the expected benefits compared to O‐FT, primarily due to delays in PCI implementation. This challenge is also prevalent in numerous developing countries. 21 Studies from India and sub‐Saharan Africa have underscored the necessity for alternative reperfusion strategies in regions lacking timely access to PCI, thereby highlighting the global disparities in health care infrastructure. 22 , 23 Our study highlights the considerable influence of health care resource allocation on reperfusion strategies, particularly in rural China, where restricted access to PCI‐capable facilities and interhospital transfer delays constitute significant obstacles to timely PCI. 24 The early initiation of FT has been demonstrated to significantly reduce mortality in patients with STEMI. This is evidenced by the findings of the FTT (Fibrinolytic Therapy Trialists') Collaborative Group, which indicated that fibrinolysis within 2 hours of symptom onset reduces mortality by ≈25%. 25 Our findings reinforce the importance of timely intervention, suggesting that in regions where rapid PCI cannot be performed, fibrinolysis should not be delayed in favor of PCI. 1 Moreover, health care systems in developing countries should focus not only on reducing time‐to‐treatment but also on improving overall access to appropriate therapies. This includes enhancing infrastructure, training health care professionals, ensuring equitable distribution of PCI‐capable hospitals, and enhancing emergency medical services and the creation of streamlined protocols for early fibrinolysis. Furthermore, investment in transport infrastructure and interhospital coordination will facilitate more rapid access to advanced care when required.
Our analyses also show that patient‐specific characteristics may influence clinical outcomes and optimal reperfusion strategies for patients with STEMI. In particular, we identified that older age (≥60 years), higher Killip classes (particularly Killip III and IV), abnormal pulse rate status, and anterior infarction location were all associated with an increased mortality risk. These factors may modify the time threshold at which PCI loses its advantage compared with FT. Therefore, individualized assessment incorporating these patient‐specific factors into clinical decision‐making could facilitate a more precise and personalized selection of reperfusion strategies, improving patient outcomes. Future clinical guidelines should explicitly emphasize the integration of these patient‐level characteristics to assist health care providers in making informed, personalized treatment decisions in real‐world clinical practice.
China's NCPCP has made significant headway in standardizing STEMI care across the country. 26 , 27 The future focus of NCPCP should be on 3 key areas to further enhance the nationwide treatment of STEMI. First, improvements must be made to the regionally coordinated care system, particularly in rural and remote areas. This will require enhanced collaboration between medical institutions and optimized referral processes to reduce DW time. The objective is to ensure that PCI can be implemented as quickly as possible, with the aim of improving patient outcomes. 28 Second, the importance of timely fibrinolysis at non‐PCI hospitals must be emphasized. It is of the utmost importance to guarantee that medical personnel are adequately trained and equipped to act promptly. Finally, when developing reperfusion strategies, it is essential to consider both patient‐specific characteristics and system‐level factors. 29 Treatment plans should be tailored according to the patient's age, condition, and available health care resources to ensure optimal treatment effectiveness.
Strengths and Limitations
The strengths of our study include the use of a large, representative data set and the application of propensity score matching to minimize confounding factors. It should be noted, however, that the study is not without limitations. First, the data were collected from voluntary reporting hospitals, which may have introduced a degree of selection bias. Nonetheless, we conducted sensitivity and subgroup analyses to further strengthen the validity and applicability of the results. Second, our analysis was based on a national STEMI registry that did not systematically collect certain clinically relevant in‐hospital outcomes, such as bleeding complications, stroke, changes in ejection fraction, and use of circulatory support. As a result, our comparison between PPCI and O‐FT was limited primarily to in‐hospital mortality, and future studies with more detailed clinical data are needed to address this gap. Third, our study did not assess the long‐term outcomes of PCI versus fibrinolysis, which could provide further insights into the optimal reperfusion strategy. Fourth, due to data limitations, our study did not include patients who underwent coronary angiography following fibrinolysis. Current guidelines recommend that patients receiving fibrinolysis undergo coronary angiography within 2 to 24 hours. Future research should focus on comparing the effectiveness of fibrinolysis combined with timely coronary angiography versus PPCI. Fifth, as an observational analysis, despite rigorous statistical adjustments, the potential for unmeasured confounding remains, which may result in overcorrection and unreliable estimates. Sixth, the sample size in certain subgroups may introduce uncertainty, resulting in the potential for overestimation or underestimation of the findings. Last, given the constraints and variations in health care systems across developing countries, further research is needed to explore how DW–DN delay impacts outcomes in different countries.
CONCLUSIONS
This study demonstrates that PPCI provides a significant mortality benefit compared with O‐FT for patients with STEMI when performed within 120 minutes of first medical contact. However, delays in PCI implementation negate this advantage, with a critical threshold identified at 119.51 minutes. In China, >40% of patients with STEMI do not benefit from the anticipated advantage of PPCI due to delays in implementation, which highlights the necessity to optimize care pathways. In cases where patients are treated at non‐PCI hospitals, it is of particular importance to observe timely fibrinolysis, especially in resource‐limited areas. It is also important to consider both patient‐specific factors, such as age and disease severity, and system‐level constraints when determining the most appropriate reperfusion strategy. Future policy should focus on the development of regionally coordinated care systems, with the objective of reducing DW times, expanding access to fibrinolysis, and creating guidelines that balance clinical and logistical factors. Moreover, updated guidelines that integrate patient‐specific considerations with system‐level constraints will be essential to optimize outcomes. These efforts are vital to bridging the gaps in STEMI care and reducing disparities in treatment among diverse health care settings globally.
Sources of Funding
Beijing Municipal Natural Science Foundation (No. 9244026, No. 9232009), National Natural Science Foundation (No. 72404011, No. 72274005), Suzhou Science and Technology Bureau Scientific Research Demonstration Project (SKY2021003), National High Level Hospital Clinical Research Funding, Scientific Research Fund of Peking University First Hospital (No. 24cz020204). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; or decision to submit the article for publication.
Disclosures
None.
Supporting information
Figures S1–S3
Acknowledgments
We thank the Headquarter of Chest Pain Centers for providing data and training in use of the data set.
Author contributions: SZ, SX, YJ, and FL developed the study design. SZ, SX, BY, and FL led data collection and interpretation. SZ, SX, BY, YJ, FL, and YH drafted and revised the manuscript. SS and ZJ reviewed and revised the manuscript. All authors read and approved the final manuscript.
This article was sent to Krishnaraj S. Rathod, MBBS, BMedSci, MRCP, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.125.041995
For Sources of Funding and Disclosures, see page 12.
Contributor Information
Yinzi Jin, Email: yzjin@bjmu.edu.cn.
Feng Liu, Email: fliu@medmail.com.cn.
Yong Huo, Email: huoyong@263.net.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figures S1–S3