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. Author manuscript; available in PMC: 2009 Apr 1.
Published in final edited form as: Am J Med. 2008 Apr;121(4):316–323. doi: 10.1016/j.amjmed.2007.11.017

Delay in Presentation and Reperfusion Therapy in ST-Elevation Myocardial Infarction

Henry H Ting *, Elizabeth H Bradley †, Yongfei Wang †, Brahmajee K Nallamothu δ, Bernard J Gersh *, Veronique L Roger *, Judith H Lichtman †, Jeptha P Curtis †, Harlan M Krumholz †
PMCID: PMC2373574  NIHMSID: NIHMS44306  PMID: 18374691

Abstract

Background

We studied the relationship between longer delays from symptom onset to hospital presentation and the use of any reperfusion therapy, door-to-balloon time, and door-to-drug time.

Methods

Cohort study of patients with ST-elevation myocardial infarction enrolled in the National Registry of Myocardial Infarction from January 1, 1995 to December 31, 2004. Delay in hospital presentation was categorized into 1 hour intervals as ≤1 hour, >1 to 2 hours, >2 to 3 hours, etc., and >11 to 12 hours. The study analyzed 3 groups: 440,398 patients for the association between delay and use of any reperfusion therapy; 67,207 patients for the association between delay and door-to-balloon time; 183,441 patients for the association between delay and door-to-drug time.

Results

In adjusted analyses, patients with longer delays between symptom onset and hospital presentation were less likely to receive any reperfusion therapy, had longer door-to-balloon times, and had longer door-to-needle times (all p<0.0001 for linear trend). For patients presenting ≤1 hour, >1 to 2 hours, and >2 to 3 hours, >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours after symptom onset, the use of any reperfusion therapy were 77%, 77%, 73%, 53%, 50%, and 46% respectively; door-to-balloon times were 99, 101, 106, 123, 125, and 123 minutes respectively; door-to-drug times were 33, 34, 36, 46, 44, and 47 minutes respectively.

Conclusions

Longer delays from symptom onset to hospital presentation were associated with reduced likelihood of receiving primary reperfusion therapy, and even among those treated, late presenters had significantly longer door-to-balloon and door-to-drug times.

Keywords: myocardial infarction, reperfusion, angioplasty, fibrinolysis, quality

Introduction

Timely reperfusion therapy with fibrinolytic therapy or primary percutaneous coronary intervention reduces infarct size and adverse clinical consequences, including mortality, for patient with ST-elevation myocardial infarction.1–11 The guidelines state that patients with ST-elevation myocardial infarction who present within 12 hours from onset of symptoms should be treated with reperfusion therapy and target a door-to-balloon time <90 minutes and door-to-drug time <30 minutes.12 Recently, quality improvement initiatives have focused attention on where hospital delays occur and strategies to reduce door-to-balloon time.13–14

Rapid and appropriate treatment with reperfusion therapy, in accordance with the guidelines, requires a consistent approach to all eligible patients. In particular, patients who are eligible for reperfusion therapy but who present later after the onset of symptoms may not elicit the same response from the health care system. According to the guidelines, recommendations for reperfusion therapy are not different for patients with ST-elevation myocardial infarction presenting earlier versus later within the 12 hours interval after the onset of symptoms.12 However, whether patients presenting later in the interval are less likely to be treated with reperfusion therapy is not known. Moreover, among those who are treated, whether there is less urgency associated with their care, resulting in longer door-to-balloon and door-to-drug times has not been documented. If present, these gaps may contribute to worse outcomes in late presenting patients. Knowledge of these patterns would emphasize the importance of earlier presentation and focus attention on logistical and system issues that contribute to lower use of any reperfusion therapy and longer delays in treatment for patients presenting later after the onset of symptoms.

To address these issues, we undertook a study to evaluate the relationship between longer delays from symptom onset to hospital presentation and the use of any reperfusion therapy, door-to-balloon time, and door-to-drug time among patients with ST-elevation myocardial infarction between 1995 to 2004 from National Registry of Myocardial Infarction. This database is ideally positioned to address this question because it is comprised of contemporary, diverse, and national data.

Methods

Study Design and Sample

The study sample included patients enrolled in National Registry of Myocardial Infarction, a voluntary, prospective registry of patients with acute myocardial infarction, from January 1, 1995 to December 31, 2004. Participating hospitals, data collection methods, verification methods, and reliability have been previously described.15–16 Criteria for diagnosis of acute myocardial infarction used the International Classification of Diseases, 9th Revision, Clinical Modifications discharge diagnosis code of 410.X1 and was confirmed with one of the following criteria: (1) two-fold or greater elevation of cardiac biomarkers; (2) electrocardiogram evidence; and (3) echocardiographic, scintigraphic, or autopsy evidence. Participating hospitals, if required, obtained Institutional Review Board approval for data abstraction.

During our study period from 1995 to 2004, there were 1,926,108 admissions for acute myocardial infarction. The following patients were excluded sequentially: patients who did not have new or presumed new ST-segment elevation in 2 or more leads or left bundle branch block on the first electrocardiogram (n=1,161,187); patients who developed symptoms for acute myocardial infarction after hospital admission date and time (n=14,433); patients who had an unknown time of symptom onset (n=173,051); patients who had a first electrocardiogram time that was not the diagnostic electrocardiogram time for ST-elevation myocardial infarction (n=71,842); patients who had an unknown time of first electrocardiogram (n=23,268); and patients who had a delay from symptom onset to hospital arrival >12 hours (n=41,929). The remaining group of 440,398 patients with ST-elevation myocardial infarction who presented to the hospital within ≤12 hours from symptom onset comprised our study population for the analysis of the association between delay and use of any reperfusion therapy.

To analyze the relationship between delay in hospital presentation and timeliness of reperfusion therapy, the following patients were additionally excluded from the previous study population: patients who were transferred-in from another hospital (n=98,064) and patients who received reperfusion therapy >12 hours after hospital arrival (n=2,491). Then, patients who did not receive primary percutaneous coronary intervention (n=272,636) were excluded to create a study group of 67,207 patients to analyze the association between delay and door-to-balloon time. Similarly, patients who did not receive fibrinolytic therapy (n=156,402) were excluded to create a study group of 183,441 patients to analyze the association between delay and door-to-drug time.

Data Collection and Measures

Delay in hospital presentation was calculated from the documented date and time of symptom onset to the documented date and time of hospital arrival. Use of any reperfusion was defined as receiving either fibrinolytic therapy or primary percutaneous coronary intervention as a primary reperfusion strategy within ≤12 hours of hospital arrival. Door-to-balloon time was defined as time from hospital arrival to first balloon inflation and door-to-drug time was defined as time from hospital arrival to administration of fibrinolytic therapy. For the outcomes of door-to-balloon time and door-to-drug time, we log transformed the outcome measures and performed parametric analysis because their distributions were skewed. To improve the clinical interpretability of the results, we converted the logged values from the models back to their original units, i.e., minutes, using geometric means17–18 and simulation with 10,000 reiterations.19 The geometric mean gives less weight to outlying values and thus better reflects the median as compared with the arithmetic mean.

To evaluate the independent effect of delay in hospital presentation on use of any reperfusion, door-to-balloon time, door-to-drug time, and in-hospital mortality, we adjusted for the following patient and hospital variables. Patient variables included: sociodemographic (age; gender; race/ethnicity classified as white, Black, Hispanic, Asian, and other; and payer type categorized as commercial insurance, Medicare only, Medicare and any other insurance, Medicaid or self pay, and other); medical history (current smoker, diabetes, hypertension, hypercholesterolemia, family history of coronary artery disease, prior myocardial infarction, prior congestive heart failure, prior percutaneous coronary intervention, prior coronary artery bypass surgery, prior stroke, prior angina, absence of chest pain at presentation, congestive heart failure at time of presentation, cardiogenic shock at presentation, systolic blood pressure <90 mmHg at presentation, heart rate >100 beats per minute at presentation); time of day and day of week at presentation (weekdays were defined as Monday to Friday and included daytime from >8am– 4pm, evening from >4pm–12midnight, and night from >12 midnight-8am; weekends were defined as Saturday and Sunday and included daytime from >8am-4pm, evening from >4pm–12midnight, and night from >12 midnight–8am). Hospital variables included: U.S. census region (West, South, Midwest, Northeast), teaching hospitals defined as participation in an accredited residency or fellowship training program, and type of cardiac facilities (interventional, interventional without surgery on site, invasive but not interventional, and non-invasive). All these variables were selected based on their clinical and statistical significance from previous studies.11,20–21

Statistical Analyses

For the outcomes of door-to-balloon time and door-to-drug time as a function of delay in hospital presentation, multivariable generalized linear models were constructed for each outcome to estimate the associations between delay in hospital presentation adjusted for all patient and hospital characteristics. The time from symptom onset to hospital presentation was categorized into 1 hour intervals as ≤1 hour, >1 to 2 hours, >2 to 3 hours, etc., and >11 to 12 hours. By introducing 11 dummy variables representing these categories into the generalized linear models (with the first category as reference group), we estimated the unadjusted outcomes and adjusted outcomes in these categories. We constructed the test of overall differences and also linear trend in outcomes among these categories in the models.

For the outcome of use of any reperfusion, multivariable logistic regression models were constructed to estimate the associations between delay in hospital presentation adjusted for all patient and hospital characteristics. The multivariate models were repeated after excluding patients who were transferred in from another hospital and after excluding patients who had documented contraindications to fibrinolytic therapy or who were treated with emergent coronary artery bypass surgery. These results were not reported separately because the direction and magnitude of the effects were similar to the prior analyses and did not change the conclusions.

For the outcome of in-hospital mortality, multivariable logistic regression models were constructed in the group of patients who were treated with primary percutaneous coronary intervention and in the group who were treated fibrinolytic therapy as the primary reperfusion strategy, and the associations between delay in hospital presentation and in-hospital mortality were estimated and adjusted for all patient and hospital characteristics as well as door-to-balloon time or door-to-drug time respectively.

Statistical analyses were performed using SAS versions 9.1 (SAS, Inc, Cary, NC) and Stata version 8.0 (Stata Corp, College Station, TX).

Results

Study Population

Baseline characteristics of the 3 groups, namely for the use of any reperfusion therapy, those treated with primary percutaneous coronary intervention, and those treated with fibrinolytic therapy are shown in Table 1. Patient and hospital characteristics were generally similar for all 3 groups with a majority being younger (age <70 years), men, and white patients. Diabetic patients comprised 18% to 21% and those with prior myocardial infarction comprised 17% to 19%. Patients treated with primary percutaneous coronary intervention were more likely to be treated during weekday daytime hours 8am-4pm (41%) or have cardiogenic shock (3%) as compared with patients treated with fibrinolytic therapy during weekday daytime (29%) or have cardiogenic shock (1%).

Table 1.

Baseline Characteristics of Study Cohorts

Cohort for Use of Any Reperfusion Therapy Cohort Treated with Primary PCI Cohort Treated with Fibrinolytic Therapy
Description # % # % # %
N 440398 100.00 67207 100.00 183441 100.00
Demographics
Age
  Age <60 182894 41.53 31719 47.20 84140 45.87
  Age 60 to 69 104765 23.79 16100 23.96 45809 24.97
  Age 70 to 79 96045 21.81 13118 19.52 37683 20.54
  Age ≥80 56694 12.87 6270 9.33 15809 8.62
Female
  No 297095 67.46 47950 71.35 127956 69.75
  Yes 143303 32.54 19257 28.65 55485 30.25
Race
  White 380685 86.44 57060 84.90 159283 86.83
  Black 21966 4.99 3626 5.40 9091 4.96
  Hispanic 12424 2.82 2114 3.15 5591 3.05
  Asian 6292 1.43 1273 1.89 2722 1.48
  Other/Unknown 19031 4.32 3134 4.66 6754 3.68
Health insurance
  Commercial (HMO/PPO) only 175229 39.79 30240 45.00 81202 44.27
  Medicare only 126381 28.70 15013 22.34 48112 26.23
  Medicare with any other insurance 57409 13.04 9024 13.43 18139 9.89
  Medicaid or Self 47604 10.81 8043 11.97 21025 11.46
  Other/Unknown 33775 7.67 4887 7.27 14963 8.16
Medical history
Current smoker
  No 279099 63.37 40743 60.62 110986 60.50
  Yes 161299 36.63 26464 39.38 72455 39.50
Diabetes
  No 348944 79.23 55174 82.10 148966 81.21
  Yes 91454 20.77 12033 17.90 34475 18.79
Prior MI
  No 355765 80.78 55932 83.22 152256 83.00
  Yes 84633 19.22 11275 16.78 31185 17.00
Hypertension
  No 226786 51.50 35316 52.55 100187 54.62
  Yes 213612 48.50 31891 47.45 83254 45.38
Hypercholesterolemia
  No 299441 67.99 43165 64.23 126308 68.85
  Yes 140957 32.01 24042 35.77 57133 31.15
Family history of CAD
  No 303735 68.97 47098 70.08 122896 66.99
  Yes 136663 31.03 20109 29.92 60545 33.01
Prior CHF
  No 411373 93.41 65058 96.80 176629 96.29
  Yes 29025 6.59 2149 3.20 6812 3.71
Prior PCI
  No 396519 90.04 57705 85.86 167642 91.39
  Yes 43879 9.96 9502 14.14 15799 8.61
Prior CABG
  No 406665 92.34 63173 94.00 171814 93.66
  Yes 33733 7.66 4034 6.00 11627 6.34
Stroke
  No 415298 94.30 64009 95.24 177402 96.71
  Yes 25100 5.70 3198 4.76 6039 3.29
Angina
  No 394263 89.52 61096 90.91 166270 90.64
  Yes 46135 10.48 6111 9.09 17171 9.36
Presentation
Chest pain at presentation
  Yes 401564 91.18 63656 94.72 176246 96.08
  No 38834 8.82 3551 5.28 7195 3.92
Cardiogenic shock
  No 431855 98.06 65159 96.95 181505 98.94
  Yes 8543 1.94 2048 3.05 1936 1.06
Systolic Blood Pressure <90 mmHg
  No 418381 95.00 63427 94.38 174956 95.37
  Yes 22017 5.00 3780 5.62 8485 4.63
Pulse >100 beats per minute
  No 375139 85.18 59612 88.70 162563 88.62
  Yes 65259 14.82 7595 11.30 20878 11.38
Current CHF
  No 381018 86.52 61275 91.17 164674 89.77
  Yes 59380 13.48 5932 8.83 18767 10.23
Time of presentation
  Weekday daytime 141476 32.12 27566 41.02 53905 29.39
  Weekday evening 86357 19.61 11168 16.62 36660 19.98
  Weekday night 81585 18.53 11293 16.80 34972 19.06
  Weekend daytime 59104 13.42 8647 12.87 25867 14.10
  Weekend evening 37670 8.55 4597 6.84 16842 9.18
  Weekend night 34206 7.77 3936 5.86 15195 8.28
Year of presentation
  1995 56930 12.93 4531 6.74 29352 16.00
  1996 59677 13.55 5967 8.88 29950 16.33
  1997 56917 12.92 6614 9.84 27697 15.10
  1998 54210 12.31 6847 10.19 22930 12.50
  1999 58760 13.34 8133 12.10 23952 13.06
  2000 44550 10.12 7194 10.70 17524 9.55
  2001 40631 9.23 8004 11.91 14797 8.07
  2002 27240 6.19 6414 9.54 8871 4.84
  2003 23604 5.36 7163 10.66 5454 2.97
  2004 17879 4.06 6340 9.43 2914 1.59
Hospital characteristics
Cardiac facilities
  Non-invasive 65567 14.89 0 0.00 46643 25.43
  Invasive but non-interventional 84848 19.27 32 0.04 60167 32.80
  Interventional 268030 60.86 61991 92.24 66274 36.13
  Interventional without OHS 21953 4.98 5184 7.71 10357 5.65
Teaching Status
  No 250987 56.99 34759 51.72 121258 66.10
  Yes 189411 43.01 32448 48.28 62183 33.90
Census division
  West 106378 24.15 19905 29.62 42967 23.42
  South 138032 31.34 19439 28.92 56683 30.90
  Mid-West 132827 30.16 23063 34.32 48301 26.33
  Northeast 63161 14.34 4800 7.14 35490 19.35
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CHF =congestive heart failure; CABG =coronary artery bypass surgery; CAD =coronary artery disease; HMO =health maintenance organization; MI= myocardial infarction; OHS =onsite heart surgery; PCI =percutaneous coronary intervention; PPO = preferred provider organization;

Multivariable Analysis of Delay and Use of Any Reperfusion

In adjusted analyses, patients with longer times between symptom onset and hospital presentation were significantly less likely to receive any reperfusion therapy (Figure 1, p<0.0001 for linear trend). For early presenters with times from symptom onset to hospital presentation of ≤1 hour, >1 to 2 hours, and >2 to 3 hours, patients with ST-elevation myocardial infarction were treated with any reperfusion therapy in 77% (reference group), 77% (odds ratio 1.0, p=0.81), and 73% (odds ratio 0.88, p<0.0001) respectively. In late presenters with times >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours, the use of any reperfusion therapy was 53% (odds ratio 0.36, p<0.0001), 50% (odds ratio 0.33, p<0.0001), and 46% (odds ratio 0.27, p<0.0001) respectively.

Figure 1.

Figure 1

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Delay in Hospital Presentation and Use of Any Reperfusion Therapy

Multivariable Analysis of Delay and Timeliness of Reperfusion Therapy

In adjusted analyses, among patients who were treated with primary percutaneous coronary intervention, those with longer time from symptom onset to hospital presentation had significantly longer door-to-balloon times (Figure 2, p<0.0001 for linear trend). For early presenters with times from symptom onset to hospital presentation of ≤1 hour, >1 to 2 hours, and >2 to 3 hours, patients were treated with door-to-balloon times of 99, 101, 106 minutes respectively. In late presenters with times of >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours, door-to-balloon times were 123, 125, and 123 minutes respectively.

Figure 2.

Figure 2

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Delay in Hospital Presentation and Door-to-Balloon Time

Among patients who received fibrinolytic therapy, those with longer delay in hospital presentation also had significantly longer door-to-drug times (Figures 3, p<0.0001 for linear trend). For time intervals from symptom onset to hospital presentation of ≤1 hour, >1 to 2 hours, >2 to 3 hours, >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours, patients were treated with door-to-drug times of 33, 34, 36, 46, 44, and 47 minutes respectively.

Figure 3.

Figure 3

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Delay in Hospital Presentation and Door-to-Drug Time

Multivariable Analysis of Delay and In-hospital Mortality

Among patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention, the time interval from symptom onset to hospital presentation was associated with increased in-hospital mortality even after adjusting for door-to-balloon time (Figure 4, p<0.0001 for linear trend). For early presenters with times from symptom onset to hospital presentation of ≤1 hour, >1 to 2 hours, and >2 to 3 hours, in-hospital mortality rates were 4.9% (reference group), 4.0% (odds ratio 0.82, p<0.0001), and 4.0% (odds ratio 0.76, p<0.0001) respectively. In comparison, late presenters with times >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours had in-hospital mortality rates of 5.4% (odds ratio 0.91, p=0.62), 6.9% (odds ratio 1.2, p=0.34), and 6.6% (odds ratio 1.2, p=0.37) respectively.

Figure 4.

Figure 4

Figure 4

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Figure 4A. Delay in Hospital Presentation and In-Hospital Mortality Among Patients Treated with Primary PCI

Figure 4B. Delay in Hospital Presentation and In-Hospital Mortality Among Patients Treated with Fibrinolytic Therapy

Among patients with ST-elevation myocardial infarction treated with fibrinolytic therapy, the time interval from symptom onset to hospital presentation was associated with increased in-hospital mortality even after adjusting for door-to-drug time (Figure 5, p<0.0001 for linear trend). For early presenters with times from symptom onset to hospital presentation of ≤1 hour, >1 to 2 hours, and >2 to 3 hours, in-hospital mortality rates were 4.1% (reference group), 4.1% (odds ratio 0.93, p=0.022), and 4.8% (odds ratio 0.98, p=0.52) respectively. In comparison, late presenters with times of >9 to 10 hours, >10 to 11 hours, and >11 to 12 hours had in-hospital mortality rates of 7.1% (odds ratio 1.5, p<0.0001), 6.7% (odds ratio 1.3, p=0.067), and 6.3% (odds ratio 1.2, p=0.17) respectively.

Discussion

In our study of patients with ST-elevation myocardial infarction spanning a 10 year period (1995–2004), we found that longer time intervals from symptom onset to hospital presentation were associated with reduced likelihood of receiving primary reperfusion therapy, and even among those treated, late presenters had significantly longer door-to-balloon and door-to-drug times. Although guidelines state that patients with ST-elevation myocardial infarction who present within 12 hours after onset of symptoms should be treated with rapid reperfusion therapy, we found longer times to hospital presentation may contribute to downstream hospital delays in administration of reperfusion therapy and consequently, delay may represent a novel risk factor associated with poorer quality of hospital care for ST-elevation myocardial infarction.

Our study is the largest contemporary report of the relationship between time from symptom onset to hospital presentation and subsequent treatment with and timeliness of reperfusion therapy and advances the existing research in several respects. Previous studies have shown that patients with longer door-to-balloon times6,11, longer door-to-drug times2, and longer total ischemic times between symptom onset and reperfusion therapy3,8 were associated with higher in-hospital mortality rates. However, our study is the first to demonstrate the independent effect of longer time intervals from symptom onset to hospital presentation among patients with ST-elevation myocardial infarction. We demonstrated that longer times to hospital presentation were associated with significantly lower use of any reperfusion therapy, longer door-to-balloon times, and longer door-to-drug times. The novel finding from our study is that longer times to hospital presentation is a risk factor for additional downstream hospital delays in treatment with and timeliness of any reperfusion therapy.

Furthermore, among patients treated with primary percutaneous coronary intervention or fibrinolytic therapy, longer times to hospital presentation were associated with increased in-hospital mortality rates, even after adjusting for other clinical factors and door-to-balloon time or door-to-drug time respectively. The high mortality rates observed among patients presenting within <2 hours of symptom onset may represent those who are at highest clinical risk such as those with cardiogenic shock. Despite the survival bias among late presenters (some late presenters who died out of hospital would not be included in this observational registry), there was still a linear trend for increased mortality rates among patients who presented late.

Possible explanations for the relationship between delay in hospital presentation and use of any reperfusion and timeliness of reperfusion therapy include: (a) patients who present early after onset of symptoms may elicit more urgency from providers to initiate reperfusion therapy; and (b) patients who present late may exhibit more atypical or no symptoms which subsequently lead to missed or late diagnosis as well as confusion or reluctance to administer reperfusion therapy. Among patients with ST-elevation myocardial infarction eligible to receive reperfusion, an optimal system of care should not exclude patients from reperfusion therapy or incur incremental delays in door-to-balloon or door-to-drug times simply because of longer times to hospital presentation.

Recently, there is great interest in strategies to reduce door-to-balloon time13 and to develop systems of care to transfer and increase number of patients who are eligible to receive primary percutaneous coronary intervention across large geographic regions.14 These innovative approaches have focused on coordinating and streamlining processes within a hospital and between hospital networks to reduce door-to-balloon time. In concert with these initiatives, reliable systems that deliver timely reperfusion to all eligible ST-elevation myocardial infarction patients should be developed regardless of the duration of delay in hospital presentation.22–23 With the knowledge that delay in hospital presentation negatively impacts use of any and timeliness in administering reperfusion therapy, attention should be focused on logistical and system issues for providers and patients. Providers should seek to eliminate hospital delays in reperfusion therapy for patients who present late after the onset of symptoms. Moreover, it will also be important to understand which patient groups are at greatest risk for longer delays24–27 as well as to evaluate novel interventions aimed at reducing delays in hospital presentation.

Acknowledgments

Funding: Research supported by grant R01 HL072575 of National Heart, Lung, and Blood Institute.

Footnotes

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