An Observational Study of Beta-Blocker Use in Patients With Chronic Obstructive Pulmonary Disease (COPD) and Acute Myocardial Infarction
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: University of Minnesota

 
 
 
 
 
An Observational Study of Beta-Blocker Use in Patients with Chronic Obstructive 
Pulmonary Disease (COPD) and Acute Myocardial Infarction 
 
Version 4.0 
 
May 20, 2020 
  
 
 

1. Introduction 
 
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide 
and a major contributor to morbidity and mortality is comorbid cardiovascular disease. COPD is 
an independent risk factor for coronary artery disease and myocardial infarction (MI) is a 
common cause of death in those with the disease.  Beta-blockers have been demonstrated to 
reduce the risk of death and reinfarction after MI and though observational studies suggest that 
this benefit extends to patients with COPD, this has not been definitively proven in randomized 
controlled trials.  Results of the recently published randomized, placebo-controlled trial, 
Metoprolol for the Prevention of Acute Exacerbations of COPD (BLOCK COPD), demonstrate 
that beta-blockers do not reduce the risk of COPD exacerbations and increase the risk of 
exacerbations requiring hospitalization raising questions about the overall risk-benefit of the 
drugs in COPD patients, including those with class I indications such as MI.  We propose a 
multicenter, observational study to examine the association between beta-blocker use and all-
cause mortality and hospitalization following MI in patients with COPD.   
2. Background 
Results and Clinical Implications of the BLOCK COPD Trial 
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and 
the majority of COPD-related morbidity, mortality and healthcare costs are driven by 
exacerbations, particularly those requiring hospitalization (1, 2).  Possible explanations for the 
failure of existing treatments to control exacerbations adequately include the fact that events may 
be triggered or made more severe by underlying cardiovascular disease(3).  Compared to age-
matched controls, COPD is associated with up to a 5-fold risk of cardiovascular disease(4) which 
is a risk factor for exacerbation (5), hospitalization for exacerbation (6), in-hospital mortality (7, 8), 
and reduced survival (9, 10).   
It is well established that beta-blockers reduce mortality in patients after myocardial infarction(11) 
and in the presence of heart failure.(12) Patients with COPD are often denied this class of 
medications, even in the presence of evidence based indications for their use, because of 
concerns about possible adverse effects on lung function.(13, 14)  This practice pattern persists 
despite multiple observational studies suggesting beta-blockers benefit patients with COPD and 
comorbid cardiovascular disease with outcomes comparable to those observed in patients without 
COPD (13, 15, 16).  Recent non-randomized studies also suggest that beta-blockers reduce the 
risk of exacerbations and mortality in patients with COPD, with or without known cardiac 
disease.(17-20)  However, these observational data are subject to biases, precluding conclusions 
about cause and effect (21).   
To address these issues, we investigated the effect of metoprolol on the risk of exacerbations in 
COPD patients at high risk for those events (ClinicalTrials.gov number: NCT02587351) (22, 23). 
We hypothesized that metoprolol would reduce the risk of exacerbations compared with placebo 
and would not adversely impact lung function, six-minute walk distance, dyspnea, or quality of 
life. 
We randomized 532 participants with a mean (±SD) age of 65.0±7.8 years and FEV1 of 41.1±16.3 
% predicted. The study was stopped early due to futility for the primary endpoint and safety 
concerns.  There was no difference in time to first exacerbation between groups and the hazard 
ratio (HR) for assignment to metoprolol was 1.05 (95%CI: 0.84-1.32; p=0.66).  Metoprolol was 
associated with a higher risk of exacerbation requiring hospitalization (HR 1.91, 95%CI: 1.29-
2.83).  Patient reported possible beta-blocker side effects were similar between groups as was 

the overall rate of non-respiratory serious adverse events. During the treatment period, we 
observed 11 deaths in the metoprolol group and 5 in the placebo group.  
 
The results of the study strongly indicate that patients with COPD and at risk for exacerbation 
should not be prescribed beta-blockers in the absence of an established indication for the drugs 
such as recent myocardial infarction or heart failure.     
 
Unanswered Questions and the Rationale for the Proposed Study 
 
As noted above, retrospective observational studies have suggested that the benefits of beta-
blockers in patients with recent myocardial infarction and heart failure extend to those with COPD 
(13, 15, 19, 24), however, this has not been prospectively confirmed and randomized trials in 
those settings may be needed to assess overall risk-benefit.  Though such trials are beyond the 
scope of the current award, we do have the opportunity to conduct a prospective, observational 
cohort study to examine cardiac and pulmonary outcomes in COPD patients hospitalized for acute 
myocardial infarction who are and are not treated with beta-blockers.   
 
Several large randomized trials published in the 1980s demonstrated the clinical efficacy of beta-
blockers following MI but COPD patients were largely excluded from these trials because of 
concerns about adverse respiratory effects.  For example, the Metoprolol in Acute Myocardial 
Infarction (MIAMI) trial excluded patients with COPD who required steroids or beta-agonists (25).  
The Beta-Blocker Heart Attack Trial (BHAT) excluded patients with both asthma and COPD if they 
required therapy (24) and the Norwegian Timolol Study excluded all patients with COPD(11).  As 
such, these data do not provide confidence that the benefits observed in patients without COPD 
extend to those with the disease, particularly those with more symptoms and requiring respiratory 
treatments.  
 
A number of observational studies examining this issue have been conducted in an effort to 
provide evidence that can guide clinician decision making but these have been limited by their 
retrospective design, poor characterization of the COPD patients enrolled, and a lack of adequate 
follow-up data about pulmonary outcomes including COPD exacerbations.      
 
Gottlieb et al. examined the medical records of more than 200,000 patients with MI as part of the 
Cooperative Cardiovascular Project (CCP) and found that though beta-blocker use was less 
common in those with underlying COPD (22% vs. 34%), the overall benefit of beta-blockers on 
mortality was comparable to that observed in those without COPD (Relative Risk (RR) 0.60; 
95%CI, 0.57-0.63).(15)  However, no information about the severity of the underlying lung disease 
was available and the possibility that healthier patients received beta-blockers cannot be 
excluded.  A second study examining data from the CCP did stratify patients with COPD based 
on whether they were receiving beta-agonists or had been treated with oral steroids or admitted 
for COPD in the year prior to their MI.(24)  In that analysis, COPD patients without these 
characteristics derived the same mortality benefit from beta-blockers as did patients without 
COPD (RR 0.85; 95%CI, 0.73-1.00) but no benefit was observed in those treated with beta-
agonists or treated for acute symptoms in the year prior.  A more recent population-based cohort 
study from the UK of 1063 patients with COPD and MI occurring between 2003 and 2008 found 
that treatment with beta-blockers in the hospital, or at the time of discharge, was associated with 
improved survival compared to no beta-blocker treatment(13).  Though this analysis adjusted for 
COPD severity as assessed by treatment, symptoms and exacerbation history, a large number 
of patients were excluded as beta-blocker treatment was viewed as contraindicated by the treating 
physician, in some cases due to COPD.  This precludes examination of outcomes in this likely 
more severely affected group.   

 
The results of our proposed observational study would provide more robust and contemporary 
data regarding the overall risk-benefit of beta-blockers in COPD patients with acute MI and 
provide preliminary data about the feasibility of recruitment for a subsequent randomized trial.   
 
3. Specific Aims 
 
Specific Aim 1.  To determine the prevalence of COPD in patients admitted to the hospital with 
an acute myocardial infarction (AMI) and to characterize the phenotypic expression and severity 
of their underlying lung disease. 
 
Patients admitted to the hospital and who undergo cardiac catheterization for an AMI will be 
identified through the electronic medical record (EMR).  Those with a diagnosis of COPD in the 
EMR will be offered participation in the study.  Baseline characterization will include 
demographics, smoking history, prior history of exacerbations in the year before admission, 
supplemental oxygen use, respiratory and cardiac medication use, comorbidities including history 
of coronary artery disease, heart failure and ejection fraction, and pulmonary function data as 
available in the EMR.  Results of this Aim will provide data about the prevalence and clinical 
characteristics of COPD in the hospitalized population with AMI in our network.  The Aim will also 
provide an estimate of the number of annual admissions for patients with COPD and AMI.      
 
Specific Aim 2. To determine the association between beta-blocker use at discharge and 
cardiopulmonary outcomes in patients with COPD and AMI. 
 
Patients with AMI and EMR-documented COPD will be followed, prospectively from the time of 
discharge using review of the electronic medical record and as local guidance permits, phone 
calls at 3 and 6 months.  We will determine the associations between beta-blocker use at 
discharge and the risk for all-cause mortality, recurrent ischemic events, and hospitalization for 
COPD exacerbation adjusting for baseline characteristics and COPD severity.  
 
4. Study Design and Methods 
a) Overview. The study is a prospective, observational study of patients admitted to the 
BLOCK COPD network hospitals with acute AMI and COPD.  Patients with will be 
identified via the EMR.  Because of the current COVID-19 pandemic and the 
possibility of limited access to hospitalized patients,  the study consists of three 
options for enrollment. Option 1 or 2 is preferable if local guidance permits.  
 
Option 1: A total of 3 visits including 1 in person visit in the hospital and 2 follow up 
phone calls with EMR review at 3 and 6 months after discharge. Sites may consider 
alternatives to in person consent and data collection including by telephone or video 
conference. 
 
Option 2: EMR review at the time of hospital admission followed by post-discharge 
telephone consent and 2 follow up phone calls with EMR review at 3 and 6 months. 
 
Option 3: EMR review at the time of hospital admission and follow-up review of the 
EMR at 3 and 6 months after discharge.  
 

b) Participant selection and eligibility. Subjects hospitalized and who undergo 
cardiac catheterization with AMI and have EMR-documented COPD will be eligible 
for participation.  The age, race, gender, smoking status and comorbidities of 
patients with who undergo cardiac catheterization for AMI but have no EMR-
documented diagnosis of COPD will be recorded but no other information will be 
collected on this population.  
 
c) Inclusion Criteria 
a. Willing and able to provide informed consent (applicable for Option 1 and 2 
only) 
b. Men and women age 35 or older 
c. Admitted to hospital from the Emergency Department or by hospital to 
hospital transfer with a primary diagnosis of AMI 
d. Undergo cardiac catheterization for AMI 
e. EMR-documented COPD  
 
d) Exclusion Criteria 
a. Cognitive disorder that in the judgment of the investigator impairs 
understanding of the study objectives or assessments (applicable for Option 
1 only) 
b. Vulnerable populations, including prisoners and pregnant women 
 
e) Consent Process. Patients admitted and who undergo cardiac catheterization for 
AMI will be identified via the EMR. If protocol Option 1 is being followed those with 
EMR-documented COPD will be approached for participation. They will be asked to 
provide written consent only after the objectives and risks of the study have been 
fully explained.   Surrogate consent will not be permitted.  The reasons for patients 
not being eligible for the study will be recorded. If protocol Option 2 is being followed 
a waiver of informed consent will be obtained from local IRBs for the initial EMR 
review and then telephone consent will be obtained after discharge.  If Option 3 is 
being followed a waiver of consent will be obtained.   
 
f) Study Visit Schedule and Assessments 
a. In-hospital visit and EMR review.  All data elements will be obtained from the 
EMR except the self-reported COPD assessment which will be obtained 
during the hospitalization and after informed consent in protocol Option 1 and 
after discharge and phone consent in protocol option 2.   
i. Demographics to include age, gender, race and ethnicity, height, 
weight 
ii. Smoking status  
iii. COPD assessment - year of diagnosis, home use of supplemental 
oxygen, self-reported history of spirometry being conducted, number 
of hospitalizations for COPD exacerbations in the year prior to 
admission, number of courses of antibiotics and/or steroids for COPD 
exacerbations in the year prior to admission. For protocol Option 1 
this will be collected via self-report utilizing a questionnaire during the 
hospitalization. For protocol Option 2, this information will be obtained 

after discharge and phone consent.  For protocol Option 3  as much of 
this information as possible will be collected from review of the EMR. 
iv. Most recent forced expiratory volume (FEV1) and forced vital capacity 
(absolute and percent predicted) from EMR if documented in the 3 
years prior to admission 
v. Comorbidity assessment to include cardiovascular disease and risk: 
history of hypertension, hyperlipidemia, coronary artery disease, prior 
MI, heart failure (ejection fraction prior to admission if available), 
percutaneous coronary intervention (PCI), coronary artery bypass 
grafting (CABG), peripheral vascular disease, stroke, diabetes 
mellitus, cirrhosis, asthma, obstructive sleep apnea, depression, 
anxiety, end-stage renal disease, cancer (type), organ transplantation 
(type)  
vi. Respiratory medication use on admission 
vii. Cardiovascular medication use on admission 
viii. Assessment of in hospital MI treatment: thrombolytics, PCI, CABG 
ix. Diagnosis of ST elevation MI (STEMI) or non-ST elevation MI 
(NSTEMI) 
x. Initial post MI ejection fraction from inpatient echocardiogram 
xi. Length of hospital stay 
xii. Length of ICU stay 
xiii. Need for intubation 
xiv. Cardiogenic shock during hospital stay 
xv. Discharge cardiovascular medications 
xvi. Discharge disposition 
b. Phone calls (Option 1 only) and EMR review at 3 and 6 months  
i. Vital status 
ii. Date and cause of death if applicable 
iii. Interval history of hospitalization and primary diagnosis (all events will 
be captured but hospitalizations for COPD exacerbations, recurrent 
MI, revascularization, or heart failure will be specifically queried 
iv. Interval history of treatment with steroids or antibiotics for 
exacerbations of COPD 
v. Beta-blocker use and reason for discontinuation, if applicable Medical 
records will be collected for all admissions  
 
g) Analytic and Statistical considerations. 
a. Analysis plan for Aim 1.  The primary objectives of Aim 1 are to determine the 
number of admissions per year for AMI at our participating institutions and the 
prevalence of COPD in that population.  These prevalence estimates will be 
calculated as a simple fraction.  We will also compare the clinical 
characteristics of COPD patients discharged on a beta-blocker versus those 
not discharged on a beta-blocker using t-tests or chi-square tests (or Fisher’s 
exact tests) as appropriate.    
b. Analysis plan for Aim 2.  For the primary analysis we will compare the risk of 
death or all-cause hospitalization at 6 months for patients with AMI and 
COPD who were discharged alive on beta-blockers to that of patients not 

discharged on beta-blockers.  Secondary analyses will include comparisons 
of rates of hospitalization for COPD exacerbations, rates of hospitalization for 
recurrent MI or revascularization or heart failure, and rates of treatment with 
steroids and/or antibiotics for exacerbations.  The primary analysis will be 
based on adjusted Kaplan–Meier survival curves that describe the probability 
remaining alive and out of hospital in those discharged versus not discharged 
on beta-blockers, while adjusting for the inverse probability of treatment 
weighting (IPTW) to reduce confounding. For all time-to-event analyses, the 
start time will be when the participant is discharged from the hospital. 
Participants will be censored at 6 months post-discharge if no event occurred. 
The comparison of clinical characteristics between treatment groups 
conducted in aim 1 will be used to inform the calculation of the IPTW. We will 
use the adjusted log-rank test to compare the two curves. As secondary 
analyses, we will use both IPTW and adjusted Cox proportional-hazards 
models to assess the association between the beta-blocker prescription and 
death or re-hospitalization.  Adjusted models will also include the covariates 
of race, sex, baseline age, smoking status, number of hospitalizations for 
COPD during the previous year, use of supplemental oxygen, presence of 
ejection fraction <40% at discharge.  Assuming adequate frequencies 
between groups, we will stratify the models by beta-blocker use at the time of 
admission, presence of asthma, STEMI vs. NSTEMI, and site. Rates of 
exacerbation will be analyzed by IPTW negative binomial regression models 
and will be used to compare annualized rates of hospitalization. 
c. Sample size and power estimates. Prior data suggests that the prevalence of 
COPD in patients admitted with acute MI is between 13 and 25% depending 
on the population studied though these data have depended primarily on 
administrative coding (13, 16, 26-28).  COPD is an independent risk factor for 
death following MI with estimates of in-hospital mortality of 12.5% versus 
8.6% in those without COPD (28).  Estimates for 1-year mortality for those 
with MI and COPD range from 14-25% versus 7-14% in those without COPD 
(29-33).  Estimates of the benefit of beta-blockers in patients with COPD vary 
widely with studies demonstrating reductions in the risk of mortality between 
9 and 50% (4, 13, 15, 16, 34).  Data regarding the risk of re-hospitalization in 
COPD patients with MI and the association with beta-blocker use is scarce.  
However, the overall rate of readmission for recurrent MI, revascularization, 
heart failure, serious bleeding, as well as respiratory causes is 1.5-2 fold 
higher in those with COPD compared to those without the disease with a 
cumulative risk at 6 months between 25 and 45% (33, 35).  Sample size 
calculations for the proposed study are therefore based on the following 
assumptions: The estimated sample size (number of patients with COPD and 
MI ) assuming: Risk of death or re-hospitalization at 6 months in patients not 
prescribed beta blockers – between 32.5 to 37.5%; risk of death or re-
hospitalization at 6 months in patients prescribed beta blockers – 25%; 
proportion of patients discharged on beta-blockers – between 45 and 85%; 
power of 80%; and type-I error of 5% is given in Table 1. With these 
assumptions our recruitment target is 500 patients with COPD and MI who 

are discharged alive.  Assuming in-hospital mortality of 12.5% (28) we plan to 
consent 571 patients to achieve this goal.  
Table 1: Estimated sample size assuming power of 80%, α=0.05, and risk of death or re-
hospitalization at 6 months of 25% in group receiving beta blockers.  
  
5. Data collection and handling. Data will be collected on study-specific case report forms 
(CRF) at each center and then data entered to the web-based system housed at the Data 
Coordinating Center (DCC) at the University of Minnesota. 
a. Study Confidentiality and Privacy. Study participants are identified by a unique 
number with a check digit for data integrity and an enrollment code consisting of 
the first letter of the participant’s last name and the last two digits of their birth 
year.  No PHI will be collected on study CRFs or transmitted to the DCC.  Any 
identifying information that could be classified as PHI will be kept separate from 
the participant CRFs in a secure environment at the clinical center accessible 
only to study staff allowed access to PHI.  Documents which contain PHI 
requested by the DCC will be properly de-identified prior to transmission so that 
no PHI can be obtained from the records.   
b. Data Security. The web-based data submission software is Oracle Application 
Server 11g Release 1. All data transmitted from the clinical sites to the DCC and 
from the DCC to the clinical sites is SSL encrypted. The cryptographic libraries 
used for SSL are designed to meet FIPS 140-2 Level 2 certification.  The website 
is secured by individual usernames and strong passwords. Non-secure ports of 
all servers are located behind the DCC network firewall and accessible only 
under the following conditions: 1) a workstation physically present in the building 
and physically connected to the network 2) granted system access to the 
database server 3) a user name and strong password for that database server 4) 
a second username and strong password for database software 5) granted 
database access to data items.  All non-essential ports of the database server 
and web servers are closed.  Only one secure (HTTPS) port on the website 
server is open outside of the firewall; this port displays the login link to the 
secured website.  
 
Clinical site staff may access individual data items for a given participant (only 
those in their own clinic) for review, but they are unable to download any 
participant data, aggregate it, cross reference an individual’s data, or view 
participant data from another clinical site via the website.   
 
Risk in group not receiving 
beta blockers 
Proportion of patients discharged on Beta-blockers 
0.4 
0.45 
0.5 
0.55 
0.6 
0.65 
0.7 
0.75 
0.8 
0.85 
0.9 
0.3 
2528 
2473 
2471 
2519 
2622 
2791 
3053 
3451 
4083 
5174 
7401 
0.325 
1139 
1119 
1122 
1148 
1200 
1283 
1409 
1600 
1901 
2420 
3478 
0.35 
648 
638 
642 
660 
692 
743 
819 
934 
1115 
1426 
2058 
0.375 
418 
413 
417 
430 
453 
488 
540 
618 
741 
951 
1379 

All servers are physically located in a secured room which is accessible only by a 
key card; currently, only two system administrators, one financial administrator, 
and the Database Administrator have access to this room.  In addition, the 
secured room is located in a secured suite which is also accessible only by key 
cards given to current University of Minnesota employees located in the suite.  
The building is locked and accessible only by University of Minnesota employees 
located in the building after business hours and on weekends.  
 
The security administrator for Oracle RDBMS and Oracle Application Server is 
the Database Administrator.  A network system administrator regularly monitors 
for occurrences of attempted access to the network by unauthorized users. Only 
the Database Administrator has access to sensitive software passwords. On-site 
backup of study data is performed nightly; off-site backups are taken twice 
weekly and stored at a secure University of Minnesota location, in a locked office 
in a secure suite.  Additional redundancy is accomplished by storing duplicate 
database data files and control files on a separate server for disaster mitigation.  
 
6. Monitoring Plan:  Monitoring to ensure the study proceeds in compliance with the 
protocol is multifaceted including real time oversight by the local PIs and regular and real 
time monitoring of entered clinical data by staff at DCC as well as by an independent 
Observational Study Monitoring Board (OSMB).  The OSMB will be made up of at least 
one cardiologist, one pulmonologist and a statistician and will meet every six months by 
teleconference.  The responsibilities of the OSMB are to track performance of individual 
centers (including possible recommendations on actions to be taken regarding any 
center that performs unsatisfactorily); monitor overall recruitment, quality control, and 
data analysis; and oversee the overall scientific direction of the study.  The DCC will 
prepare materials for the OSMB and will schedule meetings and prepare draft agendas.  
The DCC will also conduct monthly teleconferences throughout the study to review study 
enrolment and retention, procedures, adherence to protocol, and timeliness of data 
entry.  
 
7. Human subjects protection 
a. Protection against risks.  The procedures involved in this study are limited to data 
collection using questionnaires, review of EMR, and phone calls. Risks are 
limited to risks related to invasion of privacy and breach of confidentiality and are 
no greater than minimal. To protect against these risks, informed consent and will 
be obtained and filled out in private rooms and study visits will be conducted in 
private rooms (Option 1 ony).  All data will be stored on password-protected 
computers with access limited to authorized study personnel and adequate 
measures will be taken to maintain patient confidentiality at all times. All data 
collected from subjects will be labelled with a unique code that has no individually 
identifiable information. Patient information will be maintained as confidential to 
the extent permitted by law. The PI and other designated study staff (all who 
have been educated/trained on the protection of human subjects in research) will 
have access to identifiable private information of subjects, which may also be 
shared if requested with the UAB IRB, DOD, and others who are responsible for 

ensuring compliance with laws and regulations related to research, including 
OHRP. All patient identifiers will be removed prior to any data analyses, or 
summary of data for publication in peer-reviewed journals.  
 
b. Potential benefits.  There are no direct benefits to subjects who choose to 
participate in this observational study. Participants may have the satisfaction of 
participating in a research study that will potentially lead to improved treatment of 
COPD. The risks involved in the protocol are minimal, the potential benefits to 
our understanding of the overall risk-benefit of beta-blockers in COPD patients 
with acute MI are significant, and thus the overall risk-benefit favors the conduct 
of the study.  
 
c. Importance of knowledge gained.  The results of proposed Aim 1 will provide 
data about the prevalence and clinical characteristics of COPD in the 
hospitalized population with MI in our network.  The Aim will also provide an 
estimate of the number of annual admissions for patients with COPD and MI.  
Aim 2 will provide valuable information about the associations between beta-
blocker use at discharge and the risk for all-cause mortality, recurrent ischemic 
events, and hospitalization for COPD exacerbation adjusting for baseline 
characteristics and COPD severity. Even though the parent BLOCK-COPD trial 
strongly indicated that patients with COPD and at risk for exacerbation should not 
be prescribed beta-blockers in the absence of an established indication for the 
drugs such as recent myocardial infarction or heart failure, questions remain 
about their use in the latter populations. The results of our proposed 
observational study would provide more robust and contemporary data regarding 
the overall risk-benefit of beta-blockers in COPD patients with acute MI and 
provide preliminary data about the feasibility of recruitment for a subsequent 
randomized trial.   
 
 
 

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