Context Rapid time to treatment with thrombolytic therapy is associated with
lower mortality in patients with acute myocardial infarction (MI). However,
data on time to primary angioplasty and its relationship to mortality are
inconclusive.
Objective To test the hypothesis that more rapid time to reperfusion results in
lower mortality in the strategy of primary angioplasty.
Design Prospective observational study of data collected from the Second National
Registry of Myocardial Infarction between June 1994 and March 1998.
Setting A total of 661 community and tertiary care hospitals in the United States.
Subjects A cohort of 27,080 consecutive patients with acute MI associated with
ST-segment elevation or left bundle-branch block who were treated with primary
angioplasty.
Main Outcome Measure In-hospital mortality, compared by time from acute MI symptom onset
to first balloon inflation and by time from hospital arrival to first balloon
inflation (door-to-balloon time).
Results Using a multivariate logistic regression model, the adjusted odds of
in-hospital mortality did not increase significantly with increasing delay
from MI symptom onset to first balloon inflation. However, for door-to-balloon
time (median time 1 hour 56 minutes), the adjusted odds of mortality were
significantly increased by 41% to 62% for patients with door-to-balloon times
longer than 2 hours (for 121-150 minutes: odds ratio [OR], 1.41; 95% confidence
interval [CI], 1.08-1.84; P=.01; for 151-180 minutes:
OR, 1.62; 95% CI, 1.23-2.14; P<.001; and for >180
minutes: OR, 1.61; 95% CI, 1.25-2.08; P<.001).
Conclusions The relationship in our study between increased mortality and delay
in door-to-balloon time longer than 2 hours (present in nearly 50% of this
cohort) suggests that physicians and health care systems should work to minimize
door-to-balloon times and that door-to-balloon time should be considered when
choosing a reperfusion strategy. Door-to-balloon time also appears to be a
valid quality-of-care indicator.
In the treatment of acute myocardial infarction (MI), rapid time to
treatment with thrombolytic therapy and rapid achievement of reperfusion of
the infarct-related artery with thrombolytic therapy (the "open artery theory")
is beneficial.1-5
Angiographic studies have supported the link between higher 90-minute (but
not 180-minute) infarct-related artery patency and improved survival,4,6 suggesting that small differences in
time to achieving reperfusion make clinically important differences in mortality.
Primary (or "direct") angioplasty has been found to be a useful means of achieving
reperfusion in acute ST-elevation MI compared with thrombolytic therapy in
randomized clinical trials.7-10
However, no mortality benefit of primary angioplasty over thrombolysis was
observed in several registries in which the delays in performing primary angioplasty
were longer.11-14
In these studies, the time between hospital arrival and performance of the
primary angioplasty, the so-called door-to-balloon time,5
was on average between 2 and 3 hours,11-14
much longer than in the initial clinical trials.7,8
We hypothesized that, in accord with experimental15
and clinical studies,1-5
the more rapidly reperfusion is achieved with primary angioplasty the better
the survival, and conversely, that delays in achieving reperfusion would result
in higher mortality. Because prior studies of primary angioplasty have involved
only 2007 to 130016-18
patients, it has not been possible to assess reliably the effect of time delays
on mortality. We prospectively tested this hypothesis in the Second National
Registry of Myocardial Infarction (NRMI-2), which included more than 27,000
patients treated with primary angioplasty. (A list of NRMI-2 investigators
and sites is available from the data coordinating center: Ovation Research
Group, Highland Park, Ill.)
The NRMI-2 was an observational study conducted at 1474 hospitals across
the United States between June 1994 and March 1998. The protocol specified
that all consecutive patients with the diagnosis of acute MI were to be enrolled,
resulting in a total of 767,409 participants. The protocol was approved at
each participating institution, by the institutional review board where applicable.
Myocardial infarction was defined as a patient history suggestive of MI accompanied
by either creatine kinase or creatine kinase-MB fraction at least 2 times
the upper limit of normal or electrocardiographic (ECG) evidence of MI. If
enzyme or ECG data were inconclusive, alternative enzymatic, scintigraphic,
or echocardiographic evidence of MI or an International
Classification of Diseases, Ninth Revision, Clinical Modification discharge
diagnosis code of 410.00-410.92 also qualified patients for the registry.
There were no exclusion criteria.
From the total group of hospitals, 661 had the capability and performed
primary angioplasty for acute MI. The population for this analysis was prospectively
specified as patients with onset of chest pain outside of a hospital within
24 hours, which was associated with ST-segment elevation of at least 0.1 mV
in 2 or more ECG leads or left bundle-branch block, and who underwent primary
angioplasty. Data recorded on all patients included demographics, ECG findings,
a detailed timeline including time of onset of chest pain, time of arrival
at the hospital ("door" time) and time of first balloon inflation of the primary
angioplasty procedure ("balloon" time). If the exact time of the first balloon
inflation could not be obtained from the chart, the time of the start of the
catheterization/angioplasty procedure was recorded.
Patients were divided into several prespecified groups, first by time
from MI symptom onset to first balloon inflation and then by door-to-balloon
time. Baseline characteristics and mortality rates were examined across these
time categories. The primary end point of this analysis was in-hospital mortality.
Univariate analyses were conducted to evaluate differences in baseline
characteristics across the different time categories. For these analyses,
the Wald χ2 test was used to evaluate differences between dichotomous
variables.19 All statistical analyses were
performed using SAS statistical software version 6.12.20
Means were compared using a general linear model (PROC GLM in SAS), which
was formally equivalent to an analysis of variance model,21
and medians were compared using a standard nonparametric median test (NPAR1WAY)
available in SAS.
Multivariate logistic regression analyses were conducted to evaluate
the adjusted effect estimates associated with the symptom-onset-to-balloon
and door-to-balloon time variables. For these analyses, multivariate logistic
regression models were fit (using PROC LOGISTIC in SAS), for which mortality
was the dependent (outcome) variable of interest and the various baseline
characteristics were included in these models.22,23
Initial logistic regression models were fit using a forward, stepwise automated
method. Subsequent logistic regression models were developed to include clinically
as well as statistically significant covariates, and to address specific questions
of interest regarding subgroups or restricted analyses. Model fit was assessed
using the difference in the log-likelihood scores between models.
Two models were developed, one with the time variable of symptom onset
to balloon and the second with 2 mutually exclusive time intervals, symptom-onset-to-door
time and door-to-balloon time. The final logistic regression models developed
to analyze the relationship between symptom-onset-to-balloon and mortality
and door-to-balloon time and mortality included the variables shown in Table 1. The 2 models had similar odds
ratios (ORs) for the nontime variables, and thus only the model with door-to-balloon
time is shown. The OR for symptom onset to door time was 0.99 (95% confidence
interval [CI], 0.98-1.01; P=.58). Possible interactions
were also examined but no a priori interactions were posited, and inclusion
of the possible interactions between the primary exposure and other covariates
in the logistic regression model improved the overall fit as evidenced by
a statistically significant change in the log-likelihood score.
In addition to the analyses described above, a propensity score analysis
was conducted to evaluate the balance of covariates between the exposure groups.24-26
Time From Symptom Onset to Angioplasty
Among the 27,080 patients with acute ST-elevation or left bundle-branch
block MI, the median time from onset of chest pain to hospital arrival was
1.6 hours, and the median time from onset of chest pain to primary angioplasty
was 3.9 hours. Patients treated earlier were younger and more likely to be
male, to have had previous angioplasty, or presented in cardiogenic shock
(Table 2). In contrast, those
treated later were more likely to be female, diabetic, and transferred from
another institution. Although unadjusted mortality was higher in the patients
treated later, the multivariate-adjusted odds of in-hospital mortality did
not increase over the 24-hour period (Figure
1).
The median door-to-balloon time in this cohort was 1 hour 56 minutes
(interquartile range, 1 hour 25 minutes to 2 hours 43 minutes). Only 8% of
patients had a door-to-balloon time of 60 minutes or less (Table 3). Patients who underwent primary angioplasty rapidly after
hospital arrival were younger and more likely to be male. In contrast, patients
with longer door-to-balloon times more often had a contraindication to thrombolytic
therapy or were transferred from another institution.
Unadjusted mortality rose from 4.2% to 8.5% with increasing door-to-balloon
time (P<.001)
(Table 3). Controlling for differences in baseline characteristics,
the multivariate-adjusted odds of in-hospital mortality were not significantly
increased if door-to-balloon time was 2 hours or less (Figure 1). However, the adjusted odds of mortality were significantly
increased by 41% to 62% for patients with door-to-balloon times longer than
2 hours.
Subgroups and Propensity Score Analysis
No significant interactions by subgroups were observed (Table 4). For the subgroup of 22,483 patients eligible for thrombolysis,
the increases in mortality by time categories were for 121 to 150 minutes:
OR, 1.44 (P=.02); for 151 to 180 minutes: OR, 1.77
(P<.001); and for longer than 180 minutes: OR,
1.55 (P<.001). Similar increases in mortality
were observed when excluding patients transferred from other hospitals (OR,
1.37, P=.02; OR, 1.61, P=.001;
and OR, 1.47, P=.006 for the 3 time intervals, respectively).
For the 25,990 patients without cardiogenic shock, the increases in mortality
were similar to the overall group, whereas for the 988 patients in cardiogenic
shock, mortality increased more sharply as time increased (for 121-150 minutes:
OR, 1.29, P=.41; for 151-180 minutes: OR, 1.85, P=.06; and for >180 minutes: OR, 2.45, P=.003).
A propensity score analysis also was carried out.24-26
In a logistic regression model analogous to that in Table 1 that also included adjustment for the derived propensity
score, the adjusted OR for door-to-balloon time longer than 2 hours (vs <2
hours) was 1.28 (95% CI, 1.13-1.44) (P<.001).
Institutional Volume of Primary Angioplasty
Because the institutional volume of elective angioplasties performed
has been shown to influence outcome,27-30
a separate multivariate model was run that included variables for the volume
of primary angioplasty procedures performed at each
hospital, categorized as less than 1 (referent group), 1 to 3, and more than
3 per month. Interestingly, the overall adjusted mortality was lower as institutional
volume increased (Figure 2). In
the new multivariate model, when accounting for institutional volume, the
adjusted odds of mortality for door-to-balloon times longer than 2 hours were
similar to the original model.
This study demonstrates that an increase in door-to-balloon time for
primary angioplasty is associated with increased mortality. We found that
in this cohort of more than 27,000 patients treated with primary angioplasty,
the multivariate-adjusted odds of mortality were approximately 40% to 60%
higher if the door-to-balloon time was longer than 2 hours. This relationship
was observed in thrombolytic-eligible patients and when excluding patients
transferred from other hospitals or excluding those in cardiogenic shock.
The institutional volume of primary angioplasty cases appeared to independently
influence mortality, with higher volume associated with better outcomes.
It thus appears that door-to-balloon time and institutional volume of
primary angioplasty are 2 important and modifiable factors relating to survival
of patients treated with primary angioplasty. Our data suggest that physicians,
hospitals, and health care systems should work to reduce door-to-balloon time,
as has been recommended for "door-to-drug" time by the National Heart, Lung,
and Blood Institute's National Heart Attack Alert Program,3
and for primary angioplasty in the American College of Cardiology/American
Heart Association (ACC/AHA) guidelines for the management of acute MI.31,32 Our data support the current guideline
recommendation of a door-to-balloon time of 90±30 minutes.
The importance of rapid reperfusion has been established in experimental
models15 and clinical studies.1,2,4,33-37
In thrombolytic therapy, the relative benefit on mortality between tissue-type
plasminogen activator and streptokinase is believed to be due to more rapid
achievement of early patency in the infarct-related artery (ie, at 60 minutes36,38 and at 90 minutes after the start
of therapy4,36,38).
Using these findings as a foundation, the relative benefits of rapid
vs delayed primary angioplasty can be evaluated. When door-to-balloon time
is rapid (eg, 60-80 minutes as in initial trials7,8),
nearly 95% of arteries would be patent by 90 minutes after hospital arrival.
In contrast, if the door-to-balloon time is 2 hours or longer, as observed
over all 4 years in this large multicenter study, and in other registries
of current practice,11,12,39,40
patency would be achieved at the 90-minute point in only 30% to 40% of patients.39,41 Thus, door-to-balloon time would
have a profound influence on early patency of the infarct-related artery.
It is not surprising that there is no difference in mortality comparing thrombolytic
therapy with relatively delayed primary angioplasty.11,12,39,40,42,43
Based on our data, and as suggested by others,28
it appears that to afford patients the full benefit of primary angioplasty,
the door-to-balloon times should be less than 2 hours. If logistical constraints
exist (eg, need for transfer to another facility that is too far away to meet
this timeline, or nighttime delay in getting the catheterization team onsite),
immediate treatment with thrombolytic therapy in patients without contraindications
would appear to be the preferred means of reperfusion therapy. (In patients
with contraindications to thrombolysis, there is no time cut-off since primary
angioplasty is the only option.)
There also is emerging a concept of "facilitated coronary intervention"
in which patients are treated with a glycoprotein IIb/IIIa inhibitor,44,45 reduced-dose thrombolytic therapy,46 or both45,47
in the emergency department prior to transporting the patient for primary
angioplasty to achieve the benefits of earlier patency.
Quality-of-Care Indicators
Recently, door-to-drug time in patients receiving thrombolytic therapy
has been adopted as a measure of quality of care by the Joint Commission for
Accreditation of Hospitals Organization. A similar measure has been suggested
in the ACC/AHA MI guidelines for primary angioplasty, but no data were available
to support this consensus.31,32
Our data provide evidence that door-to-balloon time may be a useful marker
of quality of care for patients treated with primary angioplasty. In addition,
institutional volume of primary angioplasty cases was found to influence mortality
in acute MI, similar to observations made in elective angioplasty in other
studies.27,29,48
Thus, institutional volume of primary angioplasty may also be a useful indicator
of quality of care for hospitals.
Symptom-Onset-to-Balloon Time
An unexpected finding of our study was that adjusted mortality was not
increased with longer overall time to treatment, whereas several studies of
thrombolytic therapy have shown unadjusted2,5,33,34
and multivariate-adjusted37 mortality to be
higher with increasing time to treatment. The difference in outcome between
the 2 strategies with increasing time from symptom onset may be due to high
rates of complete reperfusion achieved by primary angioplasty in these late-presenting
patients,18 whereas artery patency is reduced
in patients treated later with thrombolysis.38,49
Interestingly, this hypothesis is supported by 2 reports in which primary
angioplasty was superior to thrombolysis in patients treated more than 4 hours
after symptom onset.9,50
Methodologically, door-to-balloon time may have emerged as predictive
while time from symptom onset was not because the latter is a much less precise
measure that depends on patient recall. In addition, there may be a difference
in ascertainment of outcomes in the 2 cohorts: for the analysis of door-to-balloon,
all patients in the cohort analysis are included in the registry, and hence
100% ascertainment of outcome is feasible. On the other hand, for time to
treatment, we do not have information in this registry on patients in the
catchment areas who had out-of-hospital MI and died prior to hospital arrival.
Hence, there may be a survivor-cohort effect, wherein those who present to
the hospital after 6 to 12 hours have already survived the highest risk period
of death, the first several hours. Thus, the denominator for the symptom-onset-to-balloon
analysis is not fully defined, whereas that for the analysis of door-to-balloon
time is a complete cohort, lending support to our findings.
Several limitations of this study should be considered. This large database
is an observational study and did not randomize patients to rapid vs slower
door-to-balloon times. However, one study has suggested that the development
of a critical pathway to reduce door-to-balloon time can improve mortality
in primary angioplasty,13 lending support to
our observations. Participation in this industry-sponsored registry was voluntary
and no independent on-site monitoring of the data was performed. However,
computer edit checks of the data were carried out and queries were sent to
the research coordinators for clarification. More importantly, the internal
validity of the NRMI-2 database has recently been demonstrated51
in a comparison of more than 25,000 patients enrolled in both NRMI-2 and the
Cooperative Cardiovascular Project, the latter of which involved rigorous
centralized chart review.52
Most hospitals in this cohort are relatively low-volume primary angioplasty
sites. However, even when accounting for hospital volume in the multivariate
model, the relationship between door-to-balloon time longer than 2 hours and
multivariate-adjusted mortality was present. It should be noted, however,
that our findings might not apply to "expert" centers with very high angioplasty
volume. Nonetheless, this 4-year, multicenter experience, involving 661 (56%)
of the 1190 hospitals in the United States that perform angioplasty, provides
a good estimate of current practice with primary angioplasty across the country.
Finally, other factors that are not captured in this database may influence
outcome,28 such as physician experience30,53,54 and angiographic
success.55
In this cohort of more than 27,000 patients treated with primary angioplasty,
door-to-balloon time longer than 2 hours was an important factor related to
mortality, a finding consistent with the pathophysiology of acute MI and prior
studies of time to treatment with thrombolysis. Given the importance of time
delays, our data suggest that physicians and health care systems should monitor
door-to-balloon times and work to reduce them to less than 2 hours. Furthermore,
when clinicians are faced with a patient having an acute MI, these data suggest
that door-to-balloon time should be considered when choosing a reperfusion
strategy.
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