Risk Stratification of Patients With Acute Anterior Myocardial Infarction and Right Bundle-Branch Block
Importance of QRS Duration and Early ST-Segment Resolution After Fibrinolytic Therapy
Background— Patients with an acute anterior ST-segment elevation myocardial infarction and right bundle-branch block (RBBB) have a high mortality risk, which may be stratified by early ECG changes.
Methods and Results— In the Hirulog Early Reperfusion Occlusion (HERO-2) trial, 17 073 patients with acute myocardial infarction (AMI) within 6 hours of symptom onset were treated with streptokinase and randomized to receive bivalirudin or heparin. There was no difference in the primary end point of 30-day mortality. ECGs were recorded at randomization and 60 minutes after fibrinolytic therapy was begun. The 30-day mortality rate was 31.6% in the 415 patients with RBBB and anterior AMI at randomization and 33% in the 100 patients who developed new RBBB at 60 minutes from normal baseline conduction accompanying an anterior AMI. An increase in QRS duration by 20-ms increments was associated with increasing 30-day mortality rate in both RBBB groups on multivariable analyses with covariates of age, Killip class, systolic blood pressure, pulse, and prior infarction. Patients with QRS duration ≥160 ms had higher 30-day mortality rate than those with QRS duration <160 ms (37.2% versus 27.2%, P=0.03, and 46.2% versus 24.5%, P=0.025, in the 2 groups, respectively). For the patients with RBBB and anterior MI at randomization, RBBB resolved at 60 minutes in 40 patients, but 30-day mortality rate was unchanged. For those with persisting RBBB at 60 minutes, 30-day mortality rate was lower if ST-segment elevation had resolved by ≥50% (20.4% versus 35.3%, P=0.006).
Conclusions— In patients with anterior AMI and RBBB, increasing QRS duration is associated with increasing 30-day mortality. Early ST-segment resolution after fibrinolytic therapy despite persisting RBBB is associated with lower mortality rate.
Received May 16, 2006; revision received June 18, 2006; accepted June 27, 2006.
Patients with right bundle-branch block (RBBB) during an anterior ST-segment elevation acute myocardial infarction (AMI) are known to have a high risk for mortality.1 In the Hirulog Early Reperfusion Occlusion (HERO-2) trial, we examined 2 groups of patients—those with RBBB at randomization and those who developed new RBBB 60 minutes after fibrinolytic therapy was begun—and confirmed a 3- to 4-fold higher 30-day mortality rate than among patients with normal intraventricular conduction.2 Whether other ECG findings would aid risk stratification was unknown.
The high risk in these patients is often due to a large anterior wall ST-elevation AMI that also involves the inter-ventricular septum, and the RBBB conduction defect reflects ischemia or necrosis of the right bundle traversing the septum. The extent of QRS prolongation varies depending on whether or not the right-bundle conduction is completely blocked and whether other parts of the conduction system are affected. Various AV nodal or fascicular blocks may also occur with RBBB.
Clinical Perspective p 789
With ST elevation during normal intraventricular conduction, higher ST-segment elevation is associated with larger potential infarct size and higher mortality,3 and ST resolution at 60 to 90 minutes after fibrinolytic therapy predicts better outcomes.4–6 However, little information is available in patients with RBBB.
The HERO-2 study randomized 17 073 patients with ST-elevation AMI within 6 hours of symptom onset to receive bivalirudin or heparin, in addition to streptokinase and aspirin. The randomized treatments had no effect on the primary end point of 30-day mortality.7 Among patients with normal intraventricular conduction, 30-day mortality was higher among those with than those without initial Q waves in the infarct leads,8 consistent with our angiographic (HERO-1) trial finding of worse epicardial recanalization, tissue reperfusion, and salvage in patients with Q waves.9–11 In the present substudy of HERO-2, we examined the cohort of patients with RBBB during anterior AMI to investigate whether QRS duration or other ECG parameters, including ST elevation and its resolution over the first 60 minutes of therapy, would help stratify patients for the risk of 30-day mortality.
The protocol of the HERO-2 trial has been reported previously.7 Patients who presented with >30 minutes of ischemic chest pain with ST elevation or presumed new left bundle-branch block within 6 hours of symptom onset were randomized to receive streptokinase and aspirin plus either bivalirudin (Hirulog) or unfractionated heparin. There was no difference in the primary end point of 30-day mortality between the 2 treatment groups.7 The trial protocol specified that ECGs were to be performed both at randomization and at 60 minutes after streptokinase was begun.8
All ECGs were sent to the core ECG laboratory at Green Lane Hospital, Auckland, New Zealand, for analysis.2,8,12 Eight experienced ECG technicians screened all trial patients to identify those with any widening of the QRS on any of the paired ECGs. These ECGs were reviewed by a cardiologist (CKW) to identify the current cohort who had bundle-branch block at either of the 2 time points.2 The present study was predefined before data lock.2
Analysis of the ECGs was performed by a cardiologist (CKW). RBBB was defined as a prolonged QRS duration ≥120 ms, with an rsr′, rsR′, or rSR′ pattern in lead V1 or V2. If this was not present, the R wave in V1 had to be notched with a prolonged R wave peak time >50 ms in V1 and normal peak time in V5 and V6. Leads V6 and I had to show a QRS complex with a wide S wave (S duration > R duration or >40 ms).2,13 Left-axis deviation during RBBB was recorded when the QRS axis was between − 45° and −120°, and right-axis deviation during RBBB was recorded when the QRS axis was from 120° to 210°.
The QRS duration was measured with a caliper in the lead with the longest QRS duration. ST segment levels were measured at the J point. Patients were classified as having anterior AMI if maximum ST elevation was present anteriorly.2 Resolution of ST elevation was calculated for the anterior lead with maximum ST elevation as the ratio of the difference in ST levels in that lead between baseline and 60 minutes over the baseline ST level.
Pathological Q waves were defined according to the recent consensus document of the Joint European Society of Cardiology/American College of Cardiology as any Q waves in leads V1 through V3, or Q waves ≥30 ms wide and ≥1 mm deep in leads I, aVL, V4, V5, or V6 that affected at least 2 contiguous leads.14
Data are presented as proportions or median values and interquartile ranges as appropriate. Comparisons between groups were by the χ2 test or Fisher exact test for categorical variables and Mann-Whitney test for continuous variables. Probability value for trend test was obtained by the Cochran-Armitage method. Multivariable logistic regression analysis incorporating clinical variables was performed to examine whether any ECG parameter would independently predict 30-day mortality in the patients with RBBB accompanying anterior AMI.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
Of 17 073 patients recruited into HERO-2, 415 had RBBB accompanying anterior AMI at randomization. Another 100 patients developed RBBB accompanying anterior AMI at 60 minutes from normal intraventricular conduction at baseline. Table 1 shows the baseline characteristics and mortality rate at 30 days (31.6% and 33%, respectively) for these 2 groups and for the patients with normal intraventricular conduction at both time points (n=15 340, 30-day mortality of 9.1%; including 7310 with anterior AMI, 30-day morality of 11.6%).
Relation Between QRS Duration and 30-Day Mortality
Increasing QRS duration by 20-ms increments was associated with increasing 30-day mortality (Figure). This was true both in the 415 patients randomized with RBBB (P<0.004) and in the 100 patients who developed new RBBB at 60 minutes (P<0.003). Patients with QRS duration ≥160 ms had higher 30-day mortality than those with QRS duration <160 ms (37.2% versus 27.2%, P=0.03, and 46.2% versus 24.5%, P=0.025, in the 2 groups, respectively).
On multivariable analysis (Table 2) with clinical parameters including age, Killip class, systolic blood pressure, heart rate, and prior infarction, increasing QRS duration by 20-ms increments independently predicted higher 30-day mortality, with an OR of 1.307 (95% CI 1.019 to 1.677) for the 415 patients randomized with RBBB and 2.023 (95% CI 1.055 to 3.88) for the 100 who developed new RBBB. The C-index of the models was 0.798 and 0.88, respectively. If only QRS duration and age were included in the model, the C-index was 0.707 and 0.831, respectively.
Prognostic Significance of Other ECG Changes During RBBB
Analyses were performed for the 2 groups of patients with RBBB accompanying anterior AMI. The magnitude of ST elevation in the anterior lead with maximum elevation was 5 mm (interquartile range 3 to 7 mm) in both groups. The magnitude of ST elevation had no relationship with 30-day mortality (Table 3).
A high proportion of patients had Q waves in the anterior AMI infarct leads (83.1% in those with RBBB at randomization and 94.0% in those who developed new RBBB at 60 minutes). There was no difference in 30-day mortality between patients with and patients without Q waves (32.8% versus 25.7%, P=0.25, and 31.9% versus 50.0%, P=0.39, in the 2 groups, respectively).
Left-axis deviation was present in 47.7% of patients with RBBB at randomization and 43% of patients with RBBB at 60 minutes. Right-axis deviation was present in 4.3% of patients with RBBB at randomization and 6% of patients with new RBBB at 60 minutes. There was no difference in 30-day mortality between patients with left-axis deviation, patients with right-axis deviation, and patients with neither (35.4% versus 22.2% versus 28.6%, P=0.243 and 39.5% versus 33.3% versus 27.5%, P=0.463, in the 3 groups, respectively). High (second- or third-)-degree AV block was present in 3 patients with RBBB at baseline and none of the patients with new RBBB at 60 minutes.
Usefulness of QRS Duration and Other ECG Parameters to Predict 30-Day Mortality
When all ECG parameters were considered when RBBB was present at randomization, as well as age, the only significant multivariable predictors of 30-day mortality were age and QRS duration (Table 4). Among the 415 patients randomized with RBBB, a QRS duration ≥160 ms predicted a higher 30-day mortality before adjustment for age (OR 1.58, 95% CI 1.04 to 2.4, P=0.03) and after adjustment for age (OR 1.85, 95% CI 1.19 to 2.87, P=0.006). In the 100 patients with new RBBB at 60 minutes, a QRS duration ≥160 ms predicted a higher 30-day mortality on univariable analysis (OR 2.63, 95% CI 1.12 to 6.2, P=0.03), and there was a trend toward higher 30-day mortality after adjustment for age (OR 2.33, 95% CI 0.87 to 6.21, P=0.09).
Resolution of RBBB at 60 Minutes and 30-Day Mortality
Among the 415 patients randomized with RBBB, the RBBB resolved to normal intraventricular conduction at 60 minutes in 40 and persisted in 365 patients. Another 2 patients developed left bundle-branch block, whereas the remaining 8 patients had suboptimal 60-minute ECGs for further interpretation (Table 5). Of the 40 patients with RBBB resolution, 7 did not have residual ST elevation ≥2 mm in the anterior lead with maximum change, and these patients had a 30-day mortality rate of 14.3%. The 33 patients who had residual anterior ST elevation ≥2 mm had a 30-day mortality rate of 39.4%.
Resolution of ST Elevation at 60 Minutes During Persistent RBBB and 30-Day Mortality
In the 365 patients in whom RBBB was present on both randomization and 60-minute ECGs, 103 had ≥50% resolution of ST-segment elevation, and 261 did not (Table 5). The 30-day mortality was 20.4% if ST segment elevation had resolved and 35.3% if ST segment had not resolved by ≥50% (P=0.006).
For patients with baseline QRS duration <160 ms, those who achieved ST resolution ≥50% had a lower 30-day mortality than patients who did not achieve ST resolution (13.9% versus 29.4%, P=0.016). For patients with a baseline QRS duration ≥160 ms, 30-day mortality was 31.6% for those who achieved ST resolution and 41.6% for those who did not (P=0.268; Table 6).
This study shows that patients with RBBB accompanying anterior AMI can be risk stratified by QRS duration when RBBB is first diagnosed and also by resolution of ST-segment elevation during RBBB at 60 minutes after fibrinolytic therapy is begun. There was an increasing 30-day mortality risk associated with increasing QRS duration in both patients randomized with RBBB and patients who developed new RBBB on a 60-minute ECG. A longer QRS duration predicted higher mortality in the clinical model with age, Killip class, systolic blood pressure, heart rate, and history of prior infarction. In contrast, neither the magnitude of anterior ST elevation nor the presence of pathological Q waves in the anterior infarct leads had any relationship with 30-day mortality.
In 34 166 patients who had normal intraventricular conduction or RBBB recruited to the GUSTO-1 (Global Utilization of Streptokinase and t-PA for Occluded coronary arteries) study, there was an association between a longer QRS duration at recruitment and a worse 30-day outcome.15 However, in the patients with RBBB recruited into GUSTO-115 (including a cohort of 289 North American patients)16 or into HERO-2, it is not known whether the QRS prolongation might have existed before the AMI or developed during the AMI. The present study adds further information about the graded prognostic relationship between QRS duration and 30-day mortality by providing data about patients who developed new RBBB by 60 minutes after having had normal intraventricular conduction at baseline. These patients had definite new-onset RBBB and provide a unique and homogeneous subset for further analysis. Of interest, the C-index of the multivariable model that used QRS duration and other parameters to predict 30-day mortality was particularly high in this group.
The right bundle branch traverses the interventricular septum toward the cardiac apex. With anterior AMI due to a very proximal left anterior descending artery occlusion, infarction or severe ischemia may damage the septum and the right bundle branch. Unlike the right bundle, the left bundle divides into multiple portions as it leaves the AV bundle, sometimes constituting a true bifascicular system with an anterosuperior branch, sometimes forming a group of central fibers, and at other times appearing as a network of fibers.17 With this variable anatomy of the left bundle branch, there are expectedly variations when ischemia or necrosis causes conduction in parts of the system to be blocked during AMI, which may explain the variable incidences and prognostic meanings of left fascicular blocks during RBBB found in previous studies.16,18,19 In the present study of patients with RBBB accompanying anterior AMI, there was no difference in 30-day mortality between those who had left-axis deviation and those who had right-axis deviation.
A wider QRS duration during RBBB may reflect more extensive damage to the conduction system (including possibly both right and left bundles) from ischemia or infarction, which would not only explain the worse outcomes but may also define an opportunity for potentially greater benefit from early aggressive reperfusion or revascularization. Interestingly, in the SHOCK trial (SHould we emergently revascularize Occluded Coronary arteries for cardiogenic shocK), in which mortality was reduced by revascularization, a prolonged QRS duration portended worse outcome in the patients randomized to medical treatment but not in those randomized to emergency revascularization.20
Unlike the patients with normal intraventricular conduction in HERO-2, in whom higher initial ST elevation was associated with higher 30-day mortality,8 there was no relationship between the amount of ST elevation and mortality in the patients with RBBB and anterior AMI. Other factors during RBBB might have affected the ST levels, and these include secondary repolarization changes after the positive rSR deflection of RBBB depressing the ST segment in the anterior leads, potentially reducing the magnitude of anterior ST elevation when an anterior AMI developed. However, resolution of ST-segment elevation with persisting RBBB after fibrinolytic therapy was still prognostically meaningful. Lower mortality was found in patients in whom ST elevation resolved by ≥50% than in patients with <50% ST resolution. This finding was more marked in those with baseline QRS duration <160 ms, in whom secondary repolarization abnormalities from RBBB would be expected to be less prominent.
We found that patients with RBBB accompanying anterior AMI frequently have pathological Q waves in the infarct leads, but high-grade AV blocks are not common. The latter finding could be related to the study design in that during high-grade AV block, patients may be unstable and hence may not have had the randomization or 60-minute ECGs performed during the AV block. Also, the HERO-2 ECG substudies excluded patients with ECGs with ventricular rhythms.2,8,12
A previous study of 178 patients with anterior AMI and RBBB who survived the first 24 hours found that mortality was high if left ventricular failure developed.18 Clinical deterioration clearly identifies patients at risk, but importantly, the window of therapeutic opportunity also narrows when deterioration becomes apparent. The high 24-hour mortality in the present study (16.9% for RBBB at baseline and 18% for new RBBB at 60 minutes, as shown in Table 1) stresses the need for early risk stratification, particularly with objective parameters such as age and ECG findings, data that are available before hospitalization. Whether primary percutaneous coronary intervention,21 with inevitable treatment delay, or prehospital therapy with fibrinolytic22 or other agents, with or without early percutaneous coronary intervention,23 represents the better therapy remains to be investigated.
High-risk patients with RBBB that accompanies anterior AMI can be risk stratified by the initial QRS duration and further risk stratified after reperfusion therapy by the occurrence of ST-segment resolution.
The authors thank the many investigators and patients who participated in the HERO-2 trial; Maggie Scott, RGON, who was global project manager for the trial; and Teena West, MSc, who provided statistical help for the HERO-2 ECG projects. We also thank Charlene Nell and Barbara Semb for excellent secretarial help.
Sources of Funding
The HERO-2 trial was funded by the Medicines Company. No additional funding was available for this substudy. Dr Stewart and Professor White received salary support from the Green Lane Research and Educational Fund.
Dr Stewart has received a research grant from the Health Research Council and National Heart Foundation of New Zealand. Dr Aylward has received research grants from the Medicines Company; he has also served on the speakers bureau and as a consultant/advisory board member of CSL Laboratories and has received honoraria from that company. Professor White has been a consultant to the Medicines Company, which funded the HERO-2 trial, and has received a research grant and honoraria from that company. The remaining authors report no conflicts.
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Patients with an acute anterior ST-segment elevation myocardial infarction and right bundle-branch block (RBBB) have high mortality rates. Risk stratification can be performed by assessment of early ECG changes. In the Hirulog Early Reperfusion Occlusion (HERO-2) trial, the 30-day mortality rate was 31.6% in the 415 patients with RBBB at randomization and 33% in the 100 patients who developed new RBBB at 60 minutes after streptokinase was begun. We measured QRS duration on the randomization ECGs and at 60 minutes. An increasing QRS duration by 20-ms increments was associated with increasing 30-day mortality in both RBBB groups on multivariable analyses with standard prognostic variables including age, Killip class, systolic blood pressure, pulse rate, and history of prior infarction. Patients with QRS duration ≥160 ms had a higher 30-day mortality than those with QRS duration <160 ms (37.2% versus 27.2%, P=0.03, and 46.2% versus 24.5%, P=0.025, in the 2 groups, respectively). For those with persisting RBBB at both randomization and 60 minutes, 30-day mortality was lower if ST-segment elevation had resolved by ≥50% at 60 minutes (20.4% versus 35.3%, P=0.006). High-risk patients with RBBB accompanying anterior AMI can be risk stratified by the initial QRS duration and further stratified by the occurrence of ST resolution after fibrinolytic therapy.
Guest Editor for this article was Alan T. Hirsch, MD.