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J Am Coll Cardiol, 2000; 36:706-712
© 2000 by the American College of Cardiology Foundation
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CLINICAL STUDY

Treatment and outcomes of left bundle-branch block patients with myocardial infarction who present without chest pain

Michael G. Shlipak, MD, MPH* {dagger}, Alan S. Go, MD{dagger} {ddagger}, Paul D. Frederick, MPH, MBA§, Judith Malmgren, PhD§, Hal V. Barron, MD, FACC{dagger} ||, John G. Canto, MD, MSPH, FACC for the National Registry of Myocardial Infarction 2 Investigators

* San Francisco VA Medical Center, San Francisco, California, USA
{dagger} University of California, San Francisco, California, USA
{ddagger} the Northern California Kaiser Division of Research, Oakland, CaliforniaUSA
§ the University of Washington Clinical Research Coordinating Center, Seattle, Washington, USA
|| the Division of Medical Affairs, Genentech, San Francisco, California, USA
the University of Alabama Medical Center, Birmingham, Alabama, USA

Manuscript received September 13, 1999; revised manuscript received March 16, 2000, accepted April 19, 2000.

Reprint requests and correspondence: Dr. Michael G. Shlipak, General Internal Medicine Section, VA Medical Center (111A1), San Francisco, California 94121
shlip{at}itsa.ucsf.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES

We sought to determine the importance of chest pain on presentation as a predictor of in-hospital treatment and mortality in myocardial infarction (MI) patients with left bundle-branch block (LBBB).

BACKGROUND

Left bundle-branch block patients have a high mortality after MI but are unlikely to receive reperfusion therapy despite evidence from clinical trials demonstrating the efficacy of thrombolytic therapy. Nearly half of MI patients with LBBB present without chest pain.

METHODS

We studied the clinical features, treatment and in-hospital survival of 29,585 patients with LBBB enrolled in the National Registry of MI 2 (June 1994 through March 1998). Multivariate logistic regression was used to assess the independent effect of chest pain on reperfusion decisions and in-hospital mortality.

RESULTS

Left bundle-branch block patients with chest pain were greater than five-fold more likely to receive reperfusion therapy (13.6% vs. 2.6%) than LBBB patients without chest pain; they were also more likely to receive aspirin, beta-adrenergic blocking agents, heparin and nitrates (all p < 0.0001). Unadjusted in-hospital mortality was 18% in patients with chest pain and 27% in patients without chest pain. Adjusting for patient characteristics reduced the odds ratio associated with the absence of chest pain from 1.47 (95% confidence interval: 1.41 to 1.54) to 1.21 (95% confidence interval: 1.12 to 1.30). The remainder of the mortality difference was caused by the undertreatment of patients without chest pain, particularly the low utilization of aspirin and beta-blockers.

CONCLUSIONS

Left bundle-branch block patients with MI who present without chest pain are less likely to receive optimal therapy and are at increased risk of death. Prompt recognition and treatment of this high-risk subgroup should improve survival.

Abbreviations and Acronyms
  ACE = angiotensin-converting enzyme
  CABG = coronary artery bypass graft surgery
  CI = confidence interval
  ECG = electrocardiogram
  LBBB = left bundle-branch block
  MI = myocardial infarction
  NRMI-2 = National Registry of Myocardial Infarction 2
  OR = odds ratio
  PTCA = percutaneous transluminal coronary angioplasty

Patients with myocardial infarction (MI) who present with left bundle-branch block (LBBB) have greater in-hospital mortality (22.6%) than patients without LBBB (13.1%) yet are less likely to receive medications or interventions known to improve survival (1–7). Physicians are especially reluctant to utilize reperfusion therapy (thrombolytic therapy or primary angioplasty) in patients with LBBB (3,8). The reason given by physicians for not utilizing reperfusion in

LBBB patients with MI was "nondiagnostic electrocardiogram (ECG)" in over half of the patients denied treatment (5). A recent study confirmed that the ECG is indeed unable to distinguish effectively MI from other diagnoses among symptomatic patients with LBBB (9). This inability to diagnose MI reliably in LBBB patients with the ECG results in delays in the recognition of the infarction and inhibits the delivery of optimal care. Furthermore, the insensitivity of the ECG criteria that have been proposed for patients with LBBB may give clinicians a false sense of security toward the LBBB patient with MI whose ECG does not fit the criteria (10,11).

The challenge of appropriately recognizing MI in patients with LBBB, who represent about 7% of patients with MI in a sample from the National Registry of MI 2 (NRMI 2), may be increased by the frequency with which they present with atypical symptoms (5). Left bundle-branch block patients with MI are older (76 vs. 68 years) and more likely to be women (50% vs. 41%) than patients with MI and without LBBB, and they have a higher prevalence of diabetes (36% vs. 26%)—all characteristics associated with an atypical presentation of MI (12–15). A recent study from NRMI 2 demonstrated that nearly half of LBBB patients with MI presented to medical attention without chest pain (compared with 30% of MI patients without LBBB) but did not address potential differences in treatment or survival in this subgroup (5).

Because appropriate therapy for MI begins with prompt recognition and intervention, we hypothesized that patients with LBBB who present without chest pain might be at even greater risk of undertreatment. These patients without chest pain may also have greater mortality than LBBB patients with chest pain, as a result of undertreatment. Using data collected in NRMI 2, which included 29,585 patients with LBBB, we compared presenting characteristics, admitting diagnosis, treatment and outcomes among LBBB patients with MI who presented with and without chest pain.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Subjects.   The NRMI 2 is a voluntary, prospective observational registry of patients admitted to over 1,470 hospitals in all 50 states in the U.S. The registry includes only patients with the diagnosis of MI and records data on in-hospital events. Our data set included 772,586 patients admitted from June 1994 to March 1998. Patients who were transferred to or from another acute care facility were excluded due to the absence of presenting characteristics or in-hospital outcomes. The diagnosis of MI required a presentation of cardiopulmonary symptoms or signs and at least one of the following: 1) total creatine kinase or creatine kinase myocardial isoenzymes at least twice the upper limit of the normal range, 2) ECG evidence of MI, 3) alternative enzymatic, scintigraphic or autopsy evidence of MI, or 4) a principal discharge diagnosis of MI (code 410.X1, International Classification of Diseases, 9th Revision, Clinical Modification). The initial ECG report included responses indicating the presence of right bundle-branch block or LBBB. The actual ECGs are not obtainable in the NRMI 2 registry. This study includes the 29,585 patients with LBBB on the initial ECG.

Data collection.   Data on each patient included in the registry are abstracted by a trained registry coordinator at each participating hospital and recorded on standardized case report forms. An independent central data collection center (ClinTrials, Inc., Lexington, Kentucky) processed the data using double-key data entry and multiple electronic data checks to ensure accuracy, consistency and completeness. Errors in case report forms were resolved before inclusion into the database (16).

Measurements.   Chest pain was defined as discomfort or pressure in the chest, arm or jaw; it was characterized as either present or absent on presentation. The presence or absence of other presenting symptoms, such as dyspnea, nausea/vomiting or palpitations, was not recorded. Other recorded variables include age, sex, race/ethnicity (white, black or other/unknown), cardiac risk factors (diabetes, hypertension, current tobacco use, family history of coronary heart disease or hypercholesterolemia), cardiovascular history (prior MI, angina, congestive heart failure, stroke, percutaneous transluminal coronary angioplasty [PTCA], coronary artery bypass graft surgery [CABG]), severity of presentation (initial heart rate, blood pressure, Killip class, MI location), admission diagnosis and hospital bed type, medications and procedures utilized in-hospital and at discharge, ejection fraction (if measured), adverse events during hospitalization (hypotension, heart failure, cardiogenic shock, recurrent ischemia and infarction) and length of hospital stay.

Outcomes of this analysis were divided into treatment measures and mortality. We considered initial reperfusion therapy strategy to include intravenous thrombolytic therapy, primary PTCA, intracoronary thrombolytic therapy or immediate CABG. We also compared utilization of medications (aspirin, beta-adrenergic blocking agents, angiotensin-converting enzyme [ACE] inhibitors, heparin, nitrates and calcium channel blockers) in the first 24 h and in-hospital revascularization procedures (CABG and PTCA). In-hospital mortality was the primary health-related outcome of this study.

Statistical analysis.   Bivariate comparisons of the differences in demographic and clinical characteristics, diagnoses and treatments given and in-hospital mortality of LBBB patients with and without chest pain were made using chi-square tests for categorical variables, t tests for continuous variables and nonparametric methods for continuous variables that were not normally distributed.

The association between the absence of chest pain and receipt of initial reperfusion therapy, independent of other patient characteristics, was evaluated using multivariate logistic regression. A forward stepwise procedure was used including variables with an independent association with reperfusion therapy at a p < 0.05 significance level.

To evaluate the independent association of absence of chest pain with in-hospital mortality, we conducted logistic regression modeling in several stages. Model 1 adjusted for demographic and comorbidity characteristics of the patients before hospital admission (age, gender, race, prior cardiovascular history and prior medical history). In Model 2, we also adjusted for characteristics of the patient’s clinical presentation, including vital signs, Killip class and admitting diagnosis. In Model 3 we added hospital bed assignment and treatments given in-hospital, including medications and selected cardiac procedures. Statistical significance was determined by a two-sided p value <0.05.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Baseline characteristics of LBBB patients with and without chest pain at presentation.   Of the 29,585 patients with LBBB and MI in the NRMI-2 registry, 15,713 (53%) reported chest pain at presentation, and 13,872 (47%) did not report chest pain. Patients with chest pain were younger and more likely to be male than patients without chest pain (Table 1). Race was similar in the two groups of patients.


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  		Table 1 Characteristics of 29,585 Patients With Left Bundle Branch Block and Myocardial Infarction at Presentation in the National Registry for Myocardial Infarction 2 (June 1, 1994–March 31, 1998)

 
Patients with chest pain were more likely to have a prior history of cardiovascular events, including MI, angina, PTCA and CABG. Patients without chest pain were more likely to have a history of congestive heart failure. The two groups of patients had similar rates of prior stroke, diabetes, hypertension and current tobacco use. Patients with chest pain were more likely to have a family history of coronary heart disease and hypercholesterolemia.

Although we lack information on the exact symptoms of the patients without chest pain, at least 65% had clinical heart failure, based on a Killip class >1 (Table 1). Compared with patients with chest pain, these patients were less likely to be Killip class 1 (51% vs. 35%) and more likely to be Killip class 3 and 4 (19% vs. 32%). The patients with chest pain had significantly higher systolic and diastolic blood pressure and lower heart rate.

Initial diagnosis and hospital bed assignment.   Myocardial infarction was the admitting diagnosis for a small proportion (20%) of the LBBB patients with MI (Table 2). However, the proportion diagnosed accurately at admission was higher for patients with chest pain (25%) than for those without chest pain (14%). The diagnosis of "unstable angina" or "rule-out MI" was given at admission to 56% of the patients with chest pain, but only 27% without chest pain. The initial diagnosis was "other" for 59% of MI patients with LBBB who did not have chest pain, but only 19% of the patients with chest pain.


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  		Table 2 Comparison of Admitting Diagnosis and Initial Hospital Bed Assignments of 29,585 Patients With LBBB and Acute MI in the National Registry for Myocardial Infarction 2 (June 1, 1994–March 31, 1998)

 
Despite the imprecision of the initial diagnosis, the vast majority of patients were admitted to intensive care or telemetry units. However, 9% of patients without chest pain were admitted to wards without cardiac monitoring, whereas only 1% of the patients with chest pain were admitted to unmonitored beds.

In-hospital treatment of LBBB patients with and without chest pain.   Although acute reperfusion therapy was uncommonly used in all LBBB patients with MI (8.4% overall), patients with chest pain were over four-fold more likely to be treated (Table 3). Even among the patients presenting within 12 h of the onset of chest pain who did not have contraindications to thrombolytic therapy (ideal candidates for reperfusion therapy), only 17% were reperfused. The reasons given by physicians for not utilizing reperfusion were similar for the two groups of patients. The primary explanation in both groups (57% overall) was "nondiagnostic ECG."


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  		Table 3 Comparison of Treatments Received by 29,585 Patients With Acute MI and LBBB With and Without Chest Pain in the National Registry for Myocardial Infarction 2 (June 1, 1994–March 31, 1998)

 
Left bundle-branch block patients who presented with chest pain were also more likely to receive appropriate medical treatment within the initial 24 h after admission (Table 3). Aspirin, beta-blockers, intravenous nitroglycerin and heparin were all more commonly administered to patients with chest pain. Utilization of ACE-inhibitors and calcium channel blockers was similar in the two groups. Patients with chest pain were more than twice as likely to receive coronary angiography, PTCA or CABG in-hospital.

Using multivariate logistic regression, we evaluated the independent association of the presence of chest pain as a predictor of reperfusion therapy in patients with LBBB. After adjusting for presenting characteristics and admitting diagnosis, patients without chest pain were four times less likely to receive reperfusion therapy (odds ratio [OR] 0.25; 0.22 to 0.29). Characteristics associated with an increased likelihood of reperfusion included previous PTCA, increasing body weight and prior diagnosis of hypercholesterolemia. Patient characteristics negatively associated with reperfusion were increasing age; female gender; black race; diabetes; prior history of MI, angina, CABG and stroke; and increased heart rate. Admission diagnosis of MI was highly associated with reperfusion; the adjusted ORs for not being reperfused ranged from 7.2 to 10.8 for patients admitted with other diagnoses. This association indicates that early diagnosis of MI led to increased reperfusion therapy.

In-hospital mortality for patients with and without chest pain.   Left bundle-branch block patients with MI who presented without chest pain had a 47% greater in-hospital mortality rate than patients with chest pain (27% vs. 18%; p < 0.001) (Table 4). Causes of death, however, were similar for the two groups of patients. The most common reported causes of death were cardiogenic shock, arrhythmias and sudden death and heart failure.


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  		Table 4 Mortality Estimates and Causes of Death for Patients With LBBB Stratified by Presence of Chest Pain in the National Registry for Myocardial Infarction 2 (June 1, 1994–March 31, 1998)

 
The increased risk for LBBB patients without chest pain varied by age category (Table 5). For patients under 65 years of age (n = 4,101), the OR was 2.86 (95% confidence interval [CI]: 2.43 to 3.42); for patients 65 to 75 (n = 7,752), the OR was 1.92 (1.71 to 2.15); and, for patients over 75 (n = 17,705), the OR for patients without chest pain was 1.30 (1.21 to 1.40). Thus, the risk associated with the absence of chest pain was particularly marked for the younger patients with lower overall mortality risk.


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  		Table 5 In-hospital Mortality of LBBB Patients With MI Stratified by Age and the Presence of Chest Pain

 
Chest pain as an independent predictor of mortality.   The unadjusted relative risk for mortality associated with the absence of chest pain was 1.47 (1.41 to 1.54) (Fig. 1). Other clinical predictors of mortality were Killip class 3 to 4 (OR = 1.72; 95% CI: 1.58 to 1.88), Killip class 2 (1.30; 95% CI: 1.20 to 1.41) and age (OR of 1.20 per 10 year increase; 1.15 to 1.24). Adjusting for patient demographic characteristics and past medical history (Model 1) did not diminish the association of chest pain absence and mortality. However, differences in the severity of the clinical presentation among LBBB patients with and without chest pain did confound the association with mortality. In Model 2, after adjusting for severity of illness characteristics, the OR associated with absence of chest pain was reduced to 1.21 (1.12 to 1.30).



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  		Figure 1 The association of the absence of chest pain with in-hospital mortality after myocardial infarction in patients with left bundle branch block. The mortality risk associated with the absence of chest pain is calculated in a series of multivariate adjustments. Model 1 is adjusted for differences in patient demographic characteristics and past medical history. Model 2 includes variables from Model 1 and adds severity of illness characteristics. Model 3 adjusts for the above variables, hospital bed assignment and medications and procedures received in-hospital.

 
Differences in the treatment of patients with and without chest pain had a large impact on survival. The treatment variable with the largest contribution to the difference in mortality between LBBB patients with and without chest pain was aspirin (OR for in-hospital survival = 0.47; 0.44 to 0.51). After adjusting for aspirin, the OR associated with the absence of chest pain was reduced to 1.11 (1.03 to 1.19). Other treatments affecting the association between presence of chest pain and in-hospital survival were (in order of effect): beta-blockers, calcium channel blockers and ACE inhibitors. After adjustment for hospital bed assignment and medications and procedures utilized in-hospital (Model 3), we found no significant association between the absence of chest pain and in-hospital mortality (OR = 1.07; 0.98 to 1.16).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
New findings.   Patients with LBBB have been demonstrated to have greater in-hospital mortality after MI (4–6,17), yet they remain severely undertreated with reperfusion (3). In this study, we found that only 17% of LBBB patients with MI presenting with chest pain who were ideal candidates for thrombolysis received reperfusion therapy. Furthermore, we identified a substantial subgroup of LBBB patients, those without chest pain at presentation, who are at even greater risk for undertreatment and for mortality in-hospital.

Association with advanced age.   The advanced age of patients with LBBB and MI, both with and without chest pain, is an important component of their increased mortality risk. The proportion of MI patients with LBBB increases with age, from 2.7% in patients <65 years of age to 10.5% in patients over 75. Elderly patients are also more likely to present with atypical symptoms and the absence of chest pain than nonelderly patients (15,18–21). However, the increased risk of both LBBB and the absence of chest pain are independent of age alone.

Other symptoms.   Although the absence of chest pain was associated with increased mortality, we are not certain what the presenting symptoms were in these patients who comprised half of all MIs in LBBB patients. Since about two thirds presented in clinical heart failure, we speculate that the vast majority presented with dyspnea. Based on Killip class and vital signs at admission, the MIs were more severe in these patients than in those who presented with chest pain.

Decreased treatment.   Despite their severe presentations, LBBB patients without chest pain were rarely admitted with a diagnosis of MI. The absence of a diagnosis of MI in LBBB patients without chest pain may have led them to be under-treated with aspirin, beta-blockers, heparin and reperfusion therapy. Not surprisingly, absence of chest pain was one of the strongest predictors for not receiving reperfusion therapy among MI patients with LBBB.

Increased mortality.   We observed a striking difference in mortality between LBBB patients with and without chest pain; patients without chest pain had a 50% greater risk of death during hospitalization. Using staged logistic regression analyses, we demonstrated that more severe presentations of these patients were only partially responsible for the observed differences in mortality. The under-treatment of patients without chest pain caused the remainder of their increased mortality. The most striking example of treatment under-utilization is aspirin, used in less than two-thirds of patients in this sample; yet, adjusted analyses indicated that this inexpensive intervention reduced the odds of in-hospital death by over 50%. Improvements in the diagnosis and treatment of LBBB patients with MI should improve their survival.

Implications.   The results of this study should direct attention toward all patients with LBBB who present to medical attention with acute cardiopulmonary symptoms. In a small prior study, we found the rate of MI to be the same (about 30%) for LBBB patients presenting to an emergency department with acute chest pain or with acute onset of dyspnea (9). Since the patients without chest pain have a comparable or higher mortality rate compared with those with chest pain, they should be identified as high risk and treated aggressively with the presumed diagnosis of MI.

The uniqueness of this study is the attention to the multiple processes of care that affect survival in patients with LBBB. No prior study has systematically evaluated the diagnosis and treatment in-hospital of a community based sample of patients with MI presenting with LBBB. The sample size of 29,585 and the distribution of patients across the country allowed us sufficient power to make definitive conclusions about the current treatment of MI patients with LBBB in the U.S.

Study limitations.   The major weakness of this study is its reliance on chart abstraction. We did not interview patients with LBBB to determine the presence and character of their chest, arm or throat discomfort. However, misclassification bias (i.e., presence of chest pain not recorded in the medical record) should have diminished any differences we observed. Our observation period is limited to the hospitalization, so we cannot make conclusions about longer-term outcomes of these patients. We also excluded patients who were transferred in or out of the participating hospitals, which could have biased our results if these patients were systematically different from LBBB patients who were not transferred. We do not know what proportion of the LBBBs were "new" or "old"; this characterization could have confounded the association between chest pain and survival, if patients without chest pain were more likely to have "new" LBBB. Lastly, our data set includes only patients who met criteria for MI. We do not have data on patients who were admitted for cardiopulmonary symptoms but did not have MI.

Conclusions.   In conclusion, we found LBBB patients with MI presenting without chest pain were less likely to be diagnosed with MI, less likely to receive appropriate medications and reperfusion therapy and more likely to die in-hospital. The mortality difference between patients with and without chest pain was primarily explained by more complicated MIs in patients without chest pain and better treatment of patients with chest pain.

Physicians and hospitals should develop strategies for the rapid recognition and treatment of all LBBB patients who present with cardiopulmonary symptoms. These strategies could include the following: 1) educating physicians of the high prevalence of atypical symptoms in LBBB patients with MI and their elevated case-fatality rate, 2) improved implementation of evidenced-based guidelines for medical treatment of MI in patients with LBBB, such as aspirin, beta-blockers and ACE inhibitors, and 3) consideration of urgent reperfusion in LBBB patients with symptoms consistent with MI.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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