European Heart Journal (2021) 42, 907–914 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehaa1058 Ischaemic heart disease

Effect of long-term beta-blocker treatment

following myocardial infarction among stable,
optimally treated patients without heart failure
in the reperfusion era: a Danish, nationwide

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cohort study
Anders Holt 1*, Paul Blanche 1,2, Bochra Zareini 1, Deepthi Rajan 1,
Mohammed El-Sheikh 1, Anne-Marie Schjerning 3, Morten Schou 1,
Christian Torp-Pedersen4,5, Patricia McGettigan 6, Gunnar H. Gislason 1,7, and
Morten Lamberts 1
1
Research Division, Department of Cardiology, Herlev and Gentofte University Hospital, Gentofte Hospitalsvej 6, Postbox 635, DK-2900 Copenhagen, Denmark; 2Department
of Biostatistics, Copenhagen University, Øster Farimagsgade 5, DK-1014 Copenhagen, Denmark; 3Department of Cardiology, Zealand University Hospital, Sygehusvej 10, DK-
4000 Roskilde, Denmark; 4Department of Cardiology, Aalborg University Hospital, Hobrovej 18-22, DK-9100 Aalborg, Denmark; 5Department of Clinical investigation and
Cardiology, Nordsjællands Hospital, Dyrehavevej 29, DK-3400 Hillerød, Denmark; 6Department of Clinical Pharmacology, William Harvey Research Institute, Charterhouse
Square Barts and the London School of Medicine and Dentistry Queen Mary University of London, London EC1M 6BQ, UK; and 7Department of Research, Danish Heart
Foundation, Vognmagergade 7, 3. sal DK-1120 Copenhagen, Denmark

Received 16 July 2020; revised 14 October 2020; editorial decision 10 December 2020; accepted 10 December 2020; online publish-ahead-of-print 11 January 2021

See page 915 for the editorial comment on this article (doi: 10.1093/eurheartj/ehaa1033)

Listen to the audio abstract of this contribution at https://dx.doi.org/10.1093/eurheartj/ehaa1058

Aims We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in sta-
ble, optimally treated myocardial infarction (MI) patients without heart failure (HF).
...................................................................................................................................................................................................
Methods Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or per-
and results cutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-
discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or
contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive,
free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite
outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differen-
ces (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26%
sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age
61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar
risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD
(95% confidence intervals)] correspondingly; 0.1% (-0.3% to 0.5%), 0.2% (-0.7% to 1.2%), and 1.2% (-0.2% to 2.7%).
...................................................................................................................................................................................................
Conclusions In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect
of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.
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* Corresponding author. Tel: þ45 22 17 66 94, Fax: þ45 39 77 76 42, Email: anders.holt.03@regionh.dk
C The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
908 A. Holt et al.

Graphical Abstract

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...................................................................................................................................................................................................

Keywords Myocardial infarction • Beta-blockers • Reperfusion era • Over-treatment • PCI

..
Introduction .. Methods
..
..
The use of long-term beta-blocker (BB) treatment following myocar- .. National registries
dial infarction (MI) in patients with preserved ejection fraction and no
..
.. The Danish population has a unique identification number which
other evidence of heart failure (HF) has been debated in the reperfu- .. enables cross-linkage of information throughout nationwide
sion era.1 The evidence of long-term cardiac protectivity relies on
.. databases.
..
older randomized clinical trials2,3 conducted before catheter-based .. The Danish National Patient Register holds information on all hospital
.. contacts, including diagnoses and procedural codes.10 The National
reperfusion was standard care and before the widespread use of sta- ..
tins and anti-platelet agents to reduce morbidity and mortality.4 .. Causes of Death Register contains the date, primary, underlying, and con-
.. tributing causes of death.11 Both registers are coded according to the
Current American guidelines advocate for 3 years of BB treatment .. International Classification of Diseases (ICD)—the 10th revision since
following MI5,6 while recent guidelines from the European Society of ..
.. 1994. The National Prescription Register holds information on date,
Cardiology acknowledge the lack of evidence for long-term BB treat- .. amount, and dose of all redeemed prescriptions coded per the
ment, recommending initiation of BB treatment, but point to an indi- ..
.. Anatomical Therapeutic Chemical (ATC) classification system12
vidual assessment regarding duration.7,8,9 .. (Supplementary material online, Table S1).
We hypothesized that long-term BB treatment beyond 3 ..
.. The Danish Civil Registration system provides data on date of birth,
months—in the reperfusion era—did not improve cardiovascular .. sex, and vital status.13 The Danish Education register provides informa-
(CV) prognosis in MI patients without HF.
.. tion about educational level.14
Effect of long-term beta-blocker treatment following myocardial infarction
Figure 1 Flow chart of the study group. ASA, acetyl salicylic-acid; BB, beta-blocker; CABG, coronary artery bypass graft; CAG, coronary arteriog-
raphy; CV, cardiovascular; HF, heart failure; MI, myocardial infarction; PCI, percutaneous coronary intervention.
..
Study population
We identified all patients aged 30–85 years with a first-time admission of
MI undergoing percutaneous coronary intervention (PCI) or coronary
angiography (CAG) between 2003 and 2018 with no history of BB treat-
ment within 1 year prior to admission (Figure 1).
Following a quarantine period of 90 days post-MI admission, we
included only patients alive and who had redeemed a prescription of
both acetyl-salicylic acid (ASA) and statins. To avoid interactions, patients
with another indication or contraindication for BB treatment were
excluded—including HF, asthma, chronic obstructive pulmonary disease
(COPD), and atrial fibrillation/flutter (AF). Patients undergoing a cardiac
procedure CAG, PCI, implantable cardioverter-defibrillator or coronary
artery bypass graft (CABG) during the quarantine period or with a prior
history thereof were also excluded (Figure 1).
Asthma, AF, and cardiac procedures were defined by a diagnosis at any
time prior to inclusion. In order to characterize patients being treated for
COPD outside of hospitals, we also defined COPD as treatment with
inhalators containing anti-muscarinic drugs. The term ‘stable and optimal-
ly treated’ refers to MI patients who undergo a catheter-based procedure
during hospitalization; who redeem a prescription of both ASA and sta-
tins within the first 30 days post-MI; and who survive the quarantine
period without a cardiac event and without developing any indications or
contraindications for BB treatment.
Definition of beta-blocker treatment
BB treatment was defined during the 90-day quarantine period follow-
ing MI admission. Patients redeeming a BB prescription within the first
30 days following discharge were categorized as exposed and patients
not redeeming a BB prescription at all during the quarantine period
were categorized as not exposed. Due to uncertainty of indication,
909
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.. patients redeeming a BB prescription from Day 31 to Day 90 in the
.. quarantine period were excluded from the study. Dosage of BB were
.. derived from the last redeemed prescription within the quarantine
..
.. period.
.. Additionally, we assessed the use of statins, ASA, and BB throughout
..
.. the follow-up period. This was defined as a redeemed prescription at 6-
.. month intervals until the composite outcome of any CV event was
.. reached or at end of follow-up. Continuous use did not influence our ex-
..
.. posure definitions to avoid immortal time bias, but we reported it to help
.. interpretation.
..
..
.. Patient characteristics
..
.. The following characteristics were defined binarily as present (prior history
.. within 5 years) at the date of first-time MI admission: stroke, peripheral arter-
.. ial disease, acute and chronic kidney disease, liver disease, gastrointestinal
..
.. bleeding and cancer (excluding non-melanoma skin cancer). Medication was
.. defined as a redeemed prescription up to 1 year prior to the start of follow-
..
.. up of the following medicaments: diuretics, anti-hypertensive drugs, antiplate-
.. let agents, nitrates and non-steroid anti-inflammatory drugs.
..
.. In order to characterize patients being treated for hypertension and
.. diabetes mellitus outside of hospitals, we defined hypertension as a com-
.. bination treatment with at least two anti-hypertensive drugs and diabetes
..
.. mellitus as treatment with a glucose-lowering drug.15
..
..
.. Outcomes
.. Primary outcomes were (i) CV death (any CV diagnosis as primary or
..
.. underlying cause of death); (ii) recurrent MI; and (iii) a composite outcome
.. of CV events (CV death, recurrent MI, first-time diagnosis of HF, stroke,
.. stable angina pectoris, PCI, CAG or CABG). Only diagnoses related to a
..
. hospitalization were used. Secondary outcomes were defined as a
910 A. Holt et al.

composite outcome of potential adverse events related to BB treatment .. Table 1 Baseline characteristics comparing patients
and included the diagnoses: claudication, hypoglycaemic episodes, ..
pacemaker-implantation, conduction blocks, or hypotension and syncope.
.. on and not on beta-blocker treatment
..
.. Characteristics No BB BB
Statistical methods .. treatment treatment
..
Patients were divided into two groups: MI patients not receiving BB treat- .. (n 5 5407) (n 5 24 770)
.. .................................................................................................
ment and MI patients receiving BB treatment. Follow-up started 3 months .. Male, n (%) 3683 (68.1) 18 523 (74.8)
(90 days) after first-time MI admission. Individuals were followed up for a ..
maximum of 33 months or until study end (31 December 2018), death, .. Age, median (IQR) 62 (54–71) 61 (52–69)
.. Educational level, n (%)
emigration, or outcome of interest—whichever came first. We used the ..
Aalen–Johansen estimator to estimate unadjusted curves of absolute risk .. Basic school, high school or 4101 (75.8) 19 603 (79.2)
.. vocational education
(AR) over time for primary and secondary outcomes. This was done pri- ..
marily to give an overview of the raw data on the outcome before fitting .. Higher education 1161 (21.5) 4487 (18.1)
..

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the multivariable model; hence, these results should be primarily inter- .. Unknown 145 (2.7) 680 (2.7)
preted as simple descriptive statistics. A multiple logistic regression model .. Procedure during admission, n (%)
was fitted to estimate standardized AR and AR differences (ARD) for each
.. CAG during admission 1413 (26.1) 3468 (14.0)
..
outcome within 33 months after follow-up start (3 years after MI admis- .. PCI within the first day 2761 (51.1) 14 795 (59.7)
sion). We used weighted estimating equations to fit the model accounting
.. PCI during admission 1233 (22.8) 6507 (26.3)
..
for censoring and competing risk of death.16 Treatment-specific weights .. Calendar year, n (%)
were computed to account for the changes in treatment prevalence during ..
.. 2003–2005 390 (7.2) 4307 (17.4)
the inclusion period. We pre-specified the adjustments for the following at .. 2006–2008 557 (10.3) 4967 (20.1)
the date of inclusion: educational level, stroke, diabetes mellitus, hyperten- ..
.. 2009–2011 719 (13.3) 5078 (20.5)
sion, peripheral arterial disease, acute and chronic kidney disease, liver dis- .. 2012–2014 1015 (18.8) 4961 (20.0)
ease, gastrointestinal bleeding, and cancer (excluding non-melanoma skin ..
.. 2015–2018 2726 (50.4) 5457 (22.0)
cancer). We also pre-specified the modelling of plausible interactions be- .. Comorbidities, n (%)
tween BB treatment and age, sex, calendar year, and procedure during ad- ..
mission to make the modelling assumptions needed for the adjustment
.. Cancer 433 (8.0) 1521 (6.1)
.. Peripheral artery disease 108 (2.0) 426 (1.7)
flexible. Standardized AR and ARD were derived from the fitted adjusted ..
models and the confidence intervals (CIs) were computed by Bootstrap.17
.. Liver disease 65 (1.2) 263 (1.1)
.. Stroke 255 (4.7) 625 (2.5)
To challenge the assumption that we adjusted sufficiently for confounding, ..
we performed several supplementary analyses using the concept of nega- .. Diabetes mellitus 595 (11.0) 1786 (7.2)
.. Hypertension 1682 (31.1) 5331 (21.5)
tive outcome controls as stated below.18 ..
We used SAS software 9.4 (SAS Institute, Inc., Cary, NC, USA) and R .. Chronic kidney disease 114 (2.1) 336 (1.4)
.. Acute kidney disease 16 (0.3) 24 (0.1)
(version 3.5.0 for Windows, R Foundation for Statistical Computing).19 ..
.. Concomitant medication, n (%)
..
Supplementary and subgroup analyses .. ACE inhibitors 1484 (27.4) 8700 (35.1)
.. Statins 5407 (100.0) 24 770 (100.0)
(1) To asses any impact of potential unregistered HF, we excluded all .. Acetylsalicylic acid 5407 (100.0) 24 770 (100.0)
patients with a redeemed prescription of loop-diuretics 1 year prior
..
.. Loop diuretics 338 (6.3) 1445 (5.8)
to inclusion. .. ADP inhibitors 4721 (87.3) 22 749 (91.8)
(2) To evaluate the risk of unmeasured confounding, we performed a
..
.. RAS inhibitors 2245 (41.5) 10 855 (43.8)
positive exposure control analysis18 with statin treatment as expos- ..
ure in place of BB treatment. To make it comparable to our main .. All diuretics 980 (18.1) 4235 (17.1)
.. Nitrates 1263 (23.4) 6194 (25.0)
analysis, we excluded patients with a redeemed prescription of sta- ..
tins (instead of BB) 1 year prior to inclusion and included only .. NSAID 1488 (27.5) 6592 (26.6)
..
patients with a redeemed prescription of ASA and BB within the .. ACE, angiotensin converting enzyme; ADP, adenosine diphosphate; BB, beta-
quarantine period of 90 days. Otherwise, the methods were identi- .. blocker; IQR, interquartile range; NSAID, non-steroid anti-inflammatory drugs;
.. RAS, renin–angiotensin system.
cal to the main analysis. We calculated AR and ARD comparing ..
patients exposed to statins with those who were not. ..
(3) To detect potential unmeasured confounding, we also made a nega-
..
..
tive outcome control analysis18 by setting diagnosis of pneumonia as .. Results
outcome for which we expected no association with BB treatment. ..
..
(4) To avoid underestimating a possible effect of BB by looking at CV .. Baseline characteristics
death only, we estimated risk of all-cause death correspondingly. ..
.. In the period 2003–2018, a total of 30 177 stable, optimally treated
..
Ethical considerations .. MI patients were included (58% acute PCI, 26% sub-acute PCI, 16%
.. CAG without intervention) and at baseline, 82% of the patients were
The study is registered and approved by the data responsible institute ..
(Region Hovedstaden, Approval number: P-2019-191) in accordance .. on BB treatment [median age (interquartile range, IQR) 61 years (52–
with the General Data Protection Regulation. In Denmark, register-based
.. 69), 75% male] and 18% were not [median age (IQR) 62 years (54–
..
studies do not require ethical approval. . 71), 68% male]. Patients not on BB treatment were slightly older and
Effect of long-term beta-blocker treatment following myocardial infarction 911

..
a history of comorbidity more prevalent. However, most differences
were small and considered clinically negligible—not including hyper-
tension, diabetes mellitus, and stroke where the differences could be
clinically relevant. Further, patients not on BB treatment were more
likely to undergo CAG without intervention, as patients on BB treat-
ment more frequently underwent acute PCI (Table 1). The propor-
tion of MI patients not started on BB treatment grew stepwise (8% in
.. 2003–2005, 10% in 2006–2008, 12% in 2009–2011, 17% in 2012–
.. 2014, 33% in 2015–2018) with increasing calendar year.
..
..
.. Medication during follow-up
..
.. By definition, all patients were on treatment with ASA and sta-
.. tins at baseline, 82% were on BB treatment. Please see
..
. Supplementary material online, Table S2 for details on type of

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Figure 2 (A–D) Unadjusted absolute risk of primary and secondary outcomes comparing BB treatment with no BB treatment. Composite outcome of
cardiovascular events including: cardiovascular death, recurrent MI, heart failure, stroke, stabile angina pectoris, and cardiac procedures. Adverse events
including: pacemaker implantation, hypoglycaemia, claudication, hypotension/syncope, and conduction blocks. BB, beta-blocker; MI, myocardial infarction.
912 A. Holt et al.

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Figure 3 Cardiovascular risk and adverse events according to BB treatment in stable, optimally treated patients following MI. Composite outcome
of CV events including; CV death, recurrent MI, heart failure, stroke, stabile angina pectoris, and cardiac procedures. BB, beta-blocker; CI, confidence
intervals; CV, cardiovascular; MI, myocardial infarction.

BB and dosage. We excluded 488 (1.6%) due to uncertainty of

.. (5.8%)] and patients on BB treatment [n = 338 (6.3%)]. The results
..
BB treatment. .. were comparable to the main analysis with ARD (95% CI) for CV
.. death [0.2% (-0.3% to 0.6%)]; recurrent MI [0.4% (-0.6% to 1.4%)];
At the end of the predefined follow-up period, 18 779 (62%) ..
patients were alive and had not suffered any event or been lost to .. and the composite outcome of CV events [1.6% (0.03–3.2%)].
.. (2) As expected, treatment with statins had a protective association
follow-up. Among patients on treatment from follow-up start, 77%, ..
75%, and 68% were still on statins, ASA, and BB, respectively .. with recurrent MI, the composite outcome of CV events and all-
.. cause death (Supplementary material online, Figures S2B–D and S3).
(Supplementary material online, Figure S1). ..
.. (3) BB treatment was not found to have any association with the nega-
.. tive control outcome of pneumonia as predicted [ARD (95% CI)
Outcomes .. -0.2% (-0.9–0.6%)].
Among patients on BB treatment, 333, 1558, and 6631 patients
..
.. (4) BB treatment was not found to be associated with a decreased risk
had an outcome of CV death, recurrent MI, or the composite .. of all-cause death compared with no BB treatment [AR (95% CI):
outcome of CV events (CV death, recurrent MI, first-time diag-
..
.. 3.1% (2.9–3.4%) and 3.5% (3.0–4.1%), respectively; ARD (95% CI):
nosis of HF, stroke, stable angina pectoris, PCI, CAG, or CABG), .. -0.4% (-1.0–0.2%)].
..
respectively. Amid patients not in BB treatment, 72, 301, and ..
1137 patients had the corresponding outcomes. Unadjusted AR ..
.. Discussion
curves were similar comparing the two exposure groups (Figure ..
2A–C). BB treatment was associated with a similar standardized .. Our main finding was that long-term BB treatment exceeding 3
..
AR of CV death, recurrent MI and the composite outcome of .. months in stable, optimally treated MI patients without HF did not
CV events compared with the patients not receiving BB treat-
.. seem to protect against CV death, recurrent MI, or a composite out-
..
ment. No difference was found when estimating the standardized .. come of CV events. This has implications for current guidelines
AR of an adverse event either (Figure 3).
..
.. where long-term BB treatment is recommended for all MI patients—
.. regardless of reperfusion and other recommended treatment.
Supplementary analyses ..
.. Guidelines are based on data from the pre-reperfusion era where
(1) Patients with a redeemed prescription of a loop diuretic were
.. several randomized trials have found BB treatment to reduce mortal-
..
equally represented among patients not on BB treatment [n = 1445 . ity in stable MI patients without HF.2,3 However, these trials were
Effect of long-term beta-blocker treatment following myocardial infarction
..
prior to the wide usage of reperfusion interventions as well as treat-
ment with statins and anti-platelet agents.4
BBs work by inhibiting catecholamines’ binding to b-1 and b-2
adrenoreceptors present in cardiac nodal tissue, conduction system
and muscle, thus reducing heart rate, conduction speed, and con-
tractility. This combination inhibits cardiac remodelling through
reduced oxygen demand; protects against developing of cardiac
arrhythmias; and provides symptomatic relief from anginal pain.20
However, swift reperfusion of the cardiac muscle following an infarc-
tion was shown to be a strong inhibitor of sympathetic activity; hence,
it has been widely speculated whether BBs are still beneficial as long-
term treatment following MI in patients undergoing e.g. thrombolysis
or PCI.21
There are contradicting results from studies of a wide range of MI
patients without HF. One meta-analysis found that a protective effect
of BB treatment before reperfusion therapy was widely available
and—in line with our results—no evidence of a protective effect of
BB in the reperfusion era.22 However, this study failed to report dif-
ferences in medication and whether a catheter-based procedure was
done or not, which makes it harder to pin-point the exact effect of
BB treatment or lack thereof. In our study, we provide individual-
level data on procedures and medical treatment on a more strictly
selected group of patients. This offers a more accurate evaluation of
the protective effect of BB treatment and improves the external gen-
eralizability of the study. It is also important to note that patients eli-
gible for randomized clinical trials often differ from ‘real-life’ patients.
Thus, it is very reassuring to find similar results in a large observation-
al study such as ours.1
Contradicting our results, Neumann et al.23 found that discontinu-
ation of BB after 1 year following MI was associated with an increased
rate of a composite end point of all-cause mortality and recurrent MI
among 74 000 patients rather similar to our study group. This study
included asthma and COPD patients and presented in their sensitivity
analysis that without these patients, the increased rate associated
with discontinuation of BB disappeared. We believe that this is im-
portant to emphasize since this points to a strong case of interaction.
BB treatment is relatively contraindicated for asthma patients24 and
COPD patients have been found to be undertreated with BB follow-
ing MI even though the protective effect amid COPD patients is well
documented.15,25 By excluding all patients with diagnoses of asthma
and COPD, we reduce the possibility of confounding by indication
and the loss of randomness regarding exposure since clinicians typic-
ally assess the indication for BB treatment differently in these
patients.15,24,25
A recent study based on Korean register data26 found reduced
rates of all-cause death among patients without HF continuing BB
treatment for more than 1 year following MI. However, only 69%,
70%, and 51% were on ASA, statins, and clopidogrel, respectively,
among patients not continuing BB treatment, contrasted by, corres-
pondingly, 95%, 95%, and 69% among patients continuing BB treat-
ment for more than 1 year. We fear that this introduces a significant
bias towards CV protectivity and might be what drives the lower haz-
ard rates.4 We find that tighter inclusion criteria and a statistical
model without multi-collinearity and collider bias17 including report-
ing of absolute risks would make the results more fit for
interpretation.
913
.. We did not find any association between BB treatment and the
.. risk of suffering an adverse event. A Cochrane meta-analysis of BB as
..
.. treatment for hypertension found a greatly elevated risk of withdraw-
.. al due to adverse events when you compare BB treatment with pla-
..
.. cebo, diuretics, or renin-angiotensin system inhibitors; hence, it
.. seems evident that adverse events pose a problem.27 Several explan-
..
.. ations could account for this: only adverse events resulting in a hos-
.. pital contact were included; adverse events could be just a daily
..
.. nuisance and not a problem patients would take to a doctor; or our
..
.. selected patients tolerate BB treatment better on average and there
.. has not been an excess number of adverse events. A qualitative study
..
.. might be needed to assess this further.
..
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..
.. Strengths and limitations
.. As a nationwide study, our results reflect contemporary, real-life set-
..
.. tings and the risk of inclusion and selection bias was minimal. To avoid
.. immortal time bias, we defined our treatment groups before looking
..
.. at long-term use and not all patients continued their treatment. This
.. is a limitation, although it is reassuring that the decline in BB use was
..
.. similar to ASA and statins and smaller than other studies looking into
..
.. CV medicine adherence.1,28
.. Correct classification of CV death in the register depends on the
..
.. correctness of the physicians’ notifications.11 Therefore, it strength-
.. ens our conclusion that we did not find a protective association be-
..
.. tween BB treatment and all-cause death either. Furthermore, it is a
.. limitation that the registers do not contain measurements of sympa-
..
.. thetic activation, e.g. heart rate, which have been shown to be a rele-
.. vant prognostic factor in MI patients in the pre-reperfusion era.29
..
.. According to guidelines throughout our study period, all included
..
.. patients should have MI as an indication for BB treatment. However,
.. we did not know why some patients were not initiated on BB treat-
..
.. ment. By selecting our patients carefully, we have increased the
.. chance of this being as random as possible (clinician’s personal prefer-
..
.. ence, patient not liking drugs, different ‘era’, etc.) and not due to con-
.. founding by indication. To assess the amount of unmeasured
..
.. confounding further, we performed a positive exposure control simi-
.. lar to the approach of negative controls,18 associating statin treat-
..
.. ment to our primary outcomes and all-cause death. Statins should
.. 4
.. carry a cardio-protective effect in patients following MI ;thus, it is
.. reassuring that we found a protective effect associated with all-cause
..
.. death, recurrent MI, and the composite outcome of CV events.
.. Likewise, we performed a negative outcome control analysis with a
..
.. diagnosis of pneumonia as outcome and found no association with
.. BB treatment—as expected. Results from both these control analy-
..
.. ses suggest that any unmeasured confounding, if present, would not
.. be expected to have a major impact on our final results, although un-
..
.. measured confounding cannot be ruled out with certainty.
..
..
.. Clinical perspectives
..
.. An increasing number of studies, including ours, find that long-term
.. BB treatment is not associated with a protective effect following MI
..
.. in the absence of HF. We believe that this could have implications on
.. current guidelines since we have taken great measures to isolate the
..
.. effect of BB treatment. The authors advise that the continuation of
.. BB treatment should be reassessed after 3 months in all stable, opti-
..
. mally treated MI patients without HF.
914 A. Holt et al.

.. myocardial infarction in patients presenting with ST-segment elevation. Eur Heart

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.. Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J,
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