To investigate the risk factors of symptomatic bradyarrhythmias in relation to β-blockers use.
doi: 10.11909/j.issn.1671-5411.2016.09.009
PMID: 27899939
This article has been cited by other articles in PMC.
Abstract
Objective
Methods
A hospital-based case-control study [228 patients: 108 with symptomatic bradyarrhythmias (cases) and 120 controls] was conducted in Sultanah Aminah Hospital, Malaysia between January 2011 and January 2014.
Results
The mean age was 61.1 ± 13.3 years with a majority of men (68.9%). Cases were likely than control to be older, hypertensive, lower body mass index and concomitant use of rate-controlling drugs (such as digoxin, verapamil, diltiazem, ivabradine or amiodarone). Significantly higher level of serum potassium, urea, creatinine and lower level of estimated glomerular filtration rate (eGFR) were observed among cases as compared to controls. On univariate analysis among patients on β-blockers, older age (crude OR: 1.07; 95% CI: 1.03–1.11, P = 0.000), hypertension (crude OR: 5.6; 95% CI: 1.51–20.72, P = 0.010), lower sodium (crude OR: 0.04; 95% CI: 0.81–0.99, P = 0.036), higher potassium (crude OR: 2.36; 95% CI: 1.31–4.26, P = 0.004) and higher urea (crude OR: 1.23; 95% CI: 1.11–1.38, P = 0.000) were associated with increased risk of symptomatic bradyarrhythmias; eGFR was inversely and significantly associated with symptomatic bradyarrhythmias in both ‘β-blockers’ (crude OR: 0.97; 95% CI: 0.96–0.98, P = 0.000) and ‘non-β-blockers’ (crude OR: 0.99; 95% CI: 0.97–0.99, P = 0.023) arms. However, eGFR was not significantly associated with symptomatic bradyarrhythmias in the final model of both ‘β-blockers’ (adjusted OR: 0.98; 95% CI: 0.96–0.98, P = 0.103) and ‘non-β-blockers’ (adjusted OR: 0.99; 95% CI: 0.97–1.01, P = 0.328) arms. Importantly, older age was a significant predictor of symptomatic bradyarrhythmias in the ‘β-blockers’ as compared to the ‘non-β-blockers’ arms (adjusted OR: 1.09; 95% CI: 1.03–1.15, P = 0.003 vs. adjusted OR: 1.03; 95% CI: 0.98–1.09, P = 0.232, respectively).
Conclusion
Older age was a significant predictor of symptomatic bradyarrhythmias in patients on β-blockers than those without β-blockers.
Keywords: Adverse drug reaction, Beta-blocker, Bradyarrhythmias, Case-control
1. Introduction
Since the introduction of β-blockers into clinical practice for more than 40 years ago, it has had a major impact on the treatment of cardiovascular and non-cardiovascular diseases. The emergence of overwhelming evidence supports the use of β-blockers particularly in treating heart failure and ischemic heart disease (IHD) as recommended by the Clinical Practice Guidelines (CPG).– Overall, the benefit gained from the use of β-blockers outweighs the potential side effect. Metoprolol, bisoprolol, carvedilol and nebivolol have been proven in reducing morbidity and mortality in heart failure,– and reported to be well tolerated in these clinical trials.,,,– Most of the available information on the incidence of bradycardia caused by β-blockers comes from heart failure randomized controlled trials (RCTs). A review article on different types of β-blockers in heart failure trials found that the incidence of bradycardia was higher among patients on β-blockers (0.4%–12%) as compared to placebo (0–5%). Importantly, in these RCTs, asymptomatic bradycardia during β-blocker therapy is not a reason for its discontinuation. However, the number of patients not tolerating a minimal β-blocker dose in clinical practice could be higher than suggested by the withdrawal rate of 0.6%–0.9% in heart failure RCTs. For instance, a baseline heart rate (HR) of less than 68 beats/min was an exclusion criterion in heart failure trials of carvedilol, metoprolol and bisoprolol.,, RCTs usually recruit highly motivated willing volunteers. They are perhaps less likely to experience or report spontaneous events as potentially drug-related. Therefore, the figures of the adverse events reported may not be representative of clinical reality.
A number of studies had reported adverse drug reaction (ADR) associated with β-blockers as a cause for hospitalization.– A retrospective cohort of older veterans found that the prevalence of most common unplanned hospitalization caused by ADR were bradycardia secondary to β-blockers and digoxin. Moreover, another study showed that cardiac iatrogenic complications were an important factor for intensive cardiac care unit admissions, and 91% of these events were bradyarrhythmias related to anti-arrhythmic agents such as β-blockers. Understandably, the side effects of bradycardia and hypotension can arise in any patient if the dosage of β-blocker is too high or escalated too rapidly. However, there are limited studies to examine the predisposing risk factors associated with the occurrence of bradyarrhythmia in patients on usual adult dose and long term use of β-blockers. Predicting which patients may develop bradyarrhythmias after the initiation of β-blockers would be advantageous in the management of patients requiring β-blockers. Identification of the risk factors helps physicians to anticipate and avoid the potential serious ADR. Therefore, the aim of the study is to investigate the hospitalized patients diagnosed with symptomatic bradyarrhythmias and its potential risk factors in relation to the use of β-blockers as compared to patient not on β-blockers.
2. Methods
2.1. Study design
This study was a single centre, case-control study conducted in Sultanah Aminah Hospital, a 989-bed tertiary care-hospital with cardiology discipline at the southern region of peninsular Malaysia, with an average admission of 80,000 patients annually. In this hospital-based study, we prospectively identified patients admitted to cardiology unit between January 2011 and January 2014 with a primary diagnosis of symptomatic bradyarrhythmias. Bradycardia is defined as a ventricular rate of less than 60 beats per minute. For the purposes of this study, symptomatic bradyarrhythmias is defined as bradycardia (reversible or non-reversible) with serious clinical manifestations (dizziness, dyspnea, syncope or fatigue) or hemodynamic instability that required hospitalization or cardiac pacemaker. The recruitment is still on-going at the time of writing. Sample size was calculated using Power and Sample Size Calculation software version 3.1.2 for an unmatched case-control study. In our cohort, the probability of exposure (presence of β-blocker use) among controls (absence of β-blocker use) is 0.5 based on the absence of odds ratio (OR) from prior studies. If the true unadjusted OR for disease (symptomatic bradyarrhythmias) in exposed subject (presence of β-blocker use) relative to unexposed subject (absence of β-blocker use) is 3.3, we will need to study at least 50 case patients and at least 50 control patients to be able to reject null hypothesis that this OR equals 1 with probability (power) 0.8. The type 1 error probability associated with this test of this null hypothesis is 0.05.
2.2. Cases
Patients 18 years and above with symptomatic bradyarrhythmias requiring hospitalization were classified as cases. Eligible cases were patients with a confirmed diagnosis of bradyarrhythmias based on a documented standard 12-lead electrocardiography (ECG) on admission at a paper speed of 25 mm/s and an amplification of 10 mm/mV. The cases were divided into two categories according to the presence or absence of β-blockers use. The ECG diagnosis of bradyarrhythmias include sinus bradycardia, first degree heart block, second degree atrioventricular (AV) block such as Mobitz type I AV block (Wenckebach block) and Mobitz type II AV block, third-degree AV block, sick sinus syndrome and others (left bundle branch block, atrial fibrillation with bradycardia). The final ECG diagnosis of every patient was evaluated by two cardiologists. The types of β-blockers used in our cohort include cardioselective β-blockers (atenolol, metoprolol and bisoprolol) and unselective β-blockers (carvedilol).
2.3. Controls
Eligible controls were patients with normal HR and ECG. Similar to cases, the controls were divided into two categories according to the presence or absence of β-blocker use from the same hospital identified from daily admissions. For each case, we enrolled a control during the same period of admission. In summary, patients were divided into four categories according to the presence or absence of symptomatic bradyarrhythmias and presence or absence of β-blocker use as shown in Table 1.
Table 1.
Two hundred twenty eight admissions of symptomatic bradyarrhythmias and controls in relation to the use of β-blockers at Sultanah Aminah hospital, January 2011 to January 2014.
Bradyarrhythmias* | Controls | |
(+) β blocker | (n = 57) | (n = 59) |
(–) β blocker | (n = 51) | (n = 61) |
*Symptomatic bradyarrhythmias (reversible or non-reversible) requiring hospitalization. (+): presence of β blocker use, (–): absence of β blocker use.
Collaboration was sought with cardiologists, general physicians, pharmacists and nurses. They were actively involved in the identification of eligible patients, ECG diagnosis and review of patient's medications. The distribution of potential risk factors and protective factors was compared between cases and controls. Data such as demographic characteristics [age, gender, ethnicity, height, weight, body mass index (BMI)], co-morbidities [cigarette smoking, diabetes mellitus (DM), hypertension, obstructive airway disease, prior heart failure, prior cerebro-vascular accident (CVA)], admission vital signs (HR, systolic blood pressure and diastolic blood pressure), ECG diagnosis, laboratory results on admission (fasting blood glucose, serum potassium, sodium, urea, creatinine, alanine aminotransferase and total cholesterol), type and dosage of β-blockers, concurrent use of rate-controlling drugs (i.e., digoxin, verapamil, diltiazem, amiodarone or ivabradine) and outcomes of bradyarrhythmias (reversibility, pacemaker implantation and in-hospital death) were extracted from the patients' records. In order to minimize selection bias, we checked every patient's identity and reference number to avoid the same patient being included twice. Only the data on first admission was being recorded. Kidney function was assessed using estimated glomerular filtration rate (eGFR), calculated on serum creatinine measurement at presentation by using the four-variable abbreviated Modification of Diet in Renal Disease (MDRD) Study equation.
For the selection of patients on β-blockers, we chose patients on regular dose of β-blocker of more than one month in order to allow a sufficient period of exposure to β-blocker and based on the recommendation that the dose of β-blockers should be titrated over a period of four weeks. The use of β-blocker was described according to the type of commonly prescribed β-blockers (i.e., atenolol, metoprolol, bisoprolol, carvedilol) and its total daily dose. We excluded patients with incomplete information on the demographic characteristics, laboratory results, ECG diagnosis and type or dosage of β-blockers. Patients on starting dose or titration dose of β-blockers were excluded from the analysis. In addition, bradyarrhythmias caused by acute myocardial infarction and hypothyroidism were excluded from our study.
All patients diagnosed with symptomatic bradyarrhythmias were admitted to the coronary care unit. If patients remained hemodynamically stable and the rhythm abnormalities resolved after elimination of precipitating factors or discontinuation of the offending drugs, no further intervention was needed. For patients with symptomatic bradyarrhythmias with hemodynamic instability, a temporary pacemaker either inserted intravenously (invasive) or transcutaneously by external pacemakers (non-invasive) were required. At the same setting, patients were investigated for reversible causative factors such as drugs effect, ischemia and electrolyte disturbances prior to the consideration of permanent cardiac pacemaker. If β-blocker was identified as the offending medicine, the drug will be temporarily or permanently discontinued at the discretion of the attending physician. Indications for permanent cardiac pacemaker implantation was based on patients' symptoms and irreversibility of bradyarrhythmias in accordance with CPG. This study was approved by the ethics committee [National Medical Research Register (NMRR)] [Medical Research Ethics Comittee approval code: NMRR-14-1803-21444 (IIR)]. Written consent was waived by ethics committee.
2.4. Statistical analysis
We assessed differences between the baseline characteristics, vital signs at presentation, laboratory results and use of β-blockers of cases and controls. Numerical data was recorded as mean ± SD for normally distributed data, and median and interquartile range for non-normally distributed data. Categorical data was expressed as frequencies and percentages. A Chi square test was used to assess differences between categorical variables; independent t-test (parametric analysis) or Mann-Whitney U test (non-parametric analysis) was used to test differences between numerical variables. We performed a univariate analysis to examine the association between case-control status and the potential risk factor on symptomatic bradyarrhythmias using binary logistic analysis. The strength of associations between case-control status and potential risk factors was analyzed using OR and 95% confidence interval (CI). Variables significant in the univariable analysis were tested for collinearity using the Chi square test for independence. A multivariable logistic regression was then constructed using the ‘enter method’ to identify potential risk factors for symptomatic bradyarrhythmias; interactions were also tested for explanatory variables. Those explanatory variables significantly associated with case/control status in the univariable analysis (P < 0.1 or crude OR > 1.5) were fitted into the multivariable logistic regression analysis to calculate the adjusted OR, in order to identify which ones were independent risk factors. P < 0.1 and crude OR >1.5 were chosen to include as many variables in the logistic model to minimize confounding. The results were reported as unadjusted (crude) and adjusted OR with 95% CI. Variables found to be significant (adjusted OR > 1 or < 1 at P value of < 0.05) was considered significant risk factor for symptomatic bradyarrhythmias. All statistical calculations were performed using the SPSS statistics software (version 20, IBM, Armonk, New York).
3. Results
Between January 2011 and January 2014, 128 patients with a diagnosis of symptomatic bradyarrthymias (cases) and 143 patients as controls were screened. We excluded 10 cases and 23 controls because of missing or incomplete information on drug dosages, demographic characteristics and laboratory results. After the exclusion, 228 patients remained for the analyses (108 cases and 120 controls). They were divided into four categories (presence or absence of symptomatic bradyarrhythmias and presence or absence of the β-blockers use) as shown in Table 1.
In our cohort, there were 116 patients on β-blockers. The main indications of β-blockers usage were hypertension (40.5%), IHD (STEMI, NSTEMI, UA and stable angina) (38.8%), congestive heart failure (CHF) (11.2%) and cardiac arrhythmias (atrial fibrillation) (9.5%). Among 108 patients diagnosed with symptomatic bradyarrhythmias, the majority were third-degree AV block (32.4%) followed by sinus bradycardia (25.0%), junctional bradycardia (14.8%), sick sinus syndrome (7.4%), Mobitz type II AV block (5.6%), 2: 1 AV block (4.6%), Mobitz type I AV block (Wenckebach block) (3.7%), first degree AV block (0.9%) and others (left bundle branch block, atrial fibrillation with bradycardia) (5.6%).
Concomitant use of rate-controlling drugs (i.e., digoxin, verapamil, diltiazem, amiodarone or ivabradine) were found in 15 patients (eight digoxin, one diltiazem, two amiodarone, and four ivabradine) in the symptomatic bradyarrhythmias arm, and five patients (one verapamil, two diltiazem, and two ivabradine) in the control arm. Digoxin was used for atrial fibrillation and CHF, diltiazem and verapamil were used mainly for hypertension, amiodarone was used for atrial fibrillation and ivabradine was used for IHD.
Table 2 shows the characteristics and risk factors of cases and controls. The mean age was 61.2 ± 13.3 years with a majority of men (69.4%). Cases were likely than control to be older (64.4 vs. 58.4 years respectively; P = 0.000), with hypertension (79% vs. 67%, respectively; P = 0.042), with lower BMI (24.2 vs. 26.1 kg/m2, respectively; P = 0.005) and concomitant use of rate-controlling drugs (13.9% vs. 4.2%, respectively; P = 0.010). The genders, smoking status, DM, obstructive airway disease and prior CVA were similar for cases and controls.
Table 2.
Characteristics and risk factors of cases and controls in relation to the use of β-blockers.
Variables | Bradyarrhythmias* (n = 108) | Controls (n = 120) | P value |
Age, yrs | 64.4 ± 13.4 | 58.4 ± 12.5 | 0.000§ |
Height, cm | 168.0 (158.0, 174.0) | 162.5 (154.5, 168.0) | 0.000# |
Weight, kg | 70.0 (59.8, 75.0) | 69.0 (59.0, 79.0) | 0.920# |
BMI, kg/m2 | 24.2 (22.4, 26.1) | 26.1 (22.6, 29.5) | 0.005# |
Male | 75 (69.4%) | 81 (67.5%) | 0.752 |
Ethnicity | 0.014 | ||
Malay | 58 (53.7%) | 45 (37.5%) | |
Non-Malayπ | 50 (46.3%) | 75 (62.5%) | |
Smoking status | 0.515 | ||
Yes (Current / Former) | 13 (12.0%)95 (88.0%) | 18 (15%)102 (85%) | |
No | |||
Hypertension | 0.042 | ||
Yes | 85 (78.7%) | 80 (66.7%) | |
No | 23 (21.3%) | 40 (33.3%) | |
Diabetes mellitus | 0.385 | ||
Yes | 53 (49.1%) | 52 (43.3%) | |
No | 55 (50.9%) | 68 (56.7%) | |
Obstructive airway disease | |||
Yes | 4 (3.7%) | 7 (5.8%) | 0.454 |
No | 104 (96.3%) | 113 (94.2%) | |
Prior CVA | 0.169 | ||
Yes | 8 (7.4%) | 4 (3.3%) | |
No | 100 (92.6%) | 116 (96.7%) | |
Concomitant use of rate-controlling drugs | |||
Yes | 15† (13.9%) | 5¥(4.2%) | 0.010 |
No | 93 (86.1%) | 115 (95.8%) |
Data are presented as mean ± SD, n (%) or median (IQR). *Symptomatic bradyarrhythmias (reversible or non-reversible) required hospitalization; πChinese, Indian, Indigenous (Orang Asli) and other non-Malaysians; §independent student t test; #Mann Whitney u test; ¶rate-controlling drugs (viz. digoxin, verapamil, diltiazem, amiodarone or ivabradine); † among 15 patients, eight patients on digoxin, one patient on diltiazem, two patients on amiodarone and four patients on ivabradine; ¥Among five patients, one patient on verapamil, two patients on diltiazem and two patients on ivabradine. BMI: body mass index; CVA: cerebro-vascular accident; IQR: interquartile range.
Table 3 shows admission vital signs, laboratory results and doses of β-blockers among cases and controls. At presentation, the mean HR (42 beats/min vs. 76 beats/min, respectively, P = 0.000) and diastolic blood pressure (69 vs. 78 mmHg, respectively, P = 0.000) were lower among cases than controls. There were significant higher level of serum potassium (4.1 vs. 3.8 mmol/L, respectively, P = 0.004), urea (7.3 vs. 5.2 mmol/L, respectively, P = 0.000), creatinine (110 vs. 81 µmol/L, respectively, P = 0.000), total cholesterol (4.3 vs. 4.8 mmol/L, respectively, P = 0.024) and lower level of eGFR (59.4 vs. 80.0 mL/min per 1.73 m2, respectively, P = 0.000) among cases as compared to controls. There were no significant differences with respect to fasting blood sugar and alanine aminotransferase between arms.
Table 3.
![Use Use](https://thumb1.shutterstock.com/display_pic_with_logo/495346/556007218/stock-photo-acebutolol-used-for-the-treatment-of-hypertension-and-arrhythmias-a-cardioselective-beta-blocker-556007218.jpg)
Vital signs, laboratory results and β-blockers doses of cases and controls.
Variables | Bradyarrhythmias* (n = 108) | Controls (n = 120) | P value |
Vital signs | |||
HR, beat/min | 42 (28, 60) | 76 (30, 160) | 0.000# |
SBP, mmHg | 137 ± 25 | 133 ± 24 | 0.227§ |
DBP mmHg | 69 ± 15 | 78 ± 13 | 0.000§ |
LVEF, % | 53 (25, 83) | 55 (20, 80) | 0.907# |
Laboratory results | |||
FBG, mmol/L | 6.2 (3.1, 26.9) | 6.5 (4.0, 25.6) | 0.360# |
Potassium, mmol/L | 4.1 (3.0, 6.8) | 3.8 (2.5, 5.4) | 0.004# |
Sodium, mmol/L | 140.0 (113.0, 159.0) | 140.0 (132.0, 147.0) | 0.162# |
Urea, mmol/L | 7.3 (1.7, 42.3) | 5.2 (1.6, 23.0) | 0.000# |
Creatinine, µmol/L | 110.0 (50.0, 191.0) | 80.5 (40.0, 119.9) | 0.000# |
eGFR, mL/minper 1.73 m2 | 59.4 ± 32.7 | 80.0 ± 28.9 | 0.000§ |
ALT, u/L | 26.0 (6.0, 977.0) | 23.0 (6.0, 224.0) | 0.407# |
TC, mmol/L | 4.3 ± 1.1 | 4.8 ± 1.3 | 0.024§ |
Data are presented as mean ± SD, or median (IQR). *Symptomatic bradyarrhythmias (reversible or non-reversible) required hospitalization; §independent student t test; #Mann Whitney U test. ALT: alanine aminotransferase; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; FBG: fasting blood glucose; HR: heart rate at admission; LVEF: left ventricular ejection fraction; SBP: systolic blood pressure; TC: total cholesterol. Fallout 4 enclave x-02 power armor mod.
Table 4 illustrated that among patients on β-blockers, an equivalent dosage profiles were observed with atenolol, carvedilol and bisoprolol in cases and controls. Analyses of drug dosages and frequencies showed that the median dosages of different type of β-blockers of both arms had not exceeded the maximum dose recommended by CPG.– However, a significant higher median total daily dose of metoprolol (200 mg) was observed in cases than controls (100 mg) (P = 0.003). Metoprolol was the most often found β-blocker in patients with symptomatic bradyarrhythmias followed by atenolol, bisoprolol and carvedilol.
Table 4.
Bradyarrhythmias* (n = 57) | Controls (n = 59) | P value# | |||||
n | Total dose per day‡ (mg) | IQR, mg | n | Total dose per day‡, mg | IQR, mg | ||
Cardioselective β-blocker | |||||||
Atenolol | 19 | 50.0 | (25.0, 100.0) | 7 | 50.0 | (50.0, 100.0) | 0.894# |
Metoprolol | 26 | 200.0 | (50.0, 400.0) | 23 | 100.0 | (50.0, 200.0) | 0.003# |
Bisoprolol | 9 | 2.5 | (1.25, 5.0) | 20 | 2.5 | (1.25, 5.0) | 0.980# |
Unselective β-blocker | |||||||
Carvedilol | 3 | 12.5 | (6.25, 25.0) | 9 | 9.4 | (6.25, 50.0) | 0.745# |
*Symptomatic bradyarrhythmias (reversible or non-reversible) required hospitalization; ‡Median and #Mann Whitney Utest compared the daily total dosages of β-blockers between cases and controls. IQR: interquartile range.
Table 5 shows univariate and Table 6 multivariate logistic regression analyses divided into presence or absence of β-blocker arms. In our logistic regression analyses, we assumed that there was a linear relationship between continuous variable (covariate) and symptomatic bradyarrhythmias (dependent variable) in univariate and multivariate calculations. In the ‘presence of β-blocker’ arm, Table 5 showed ‘Malay versus non-Malay’ (crude OR: 2.05; 95% CI: 0.96–4.38, P = 0.064), hypertension (crude OR: 5.6; 95% CI: 1.51–20.72, P = 0.010), lower sodium (crude OR: 0.04; 95% CI: 0.81–0.99, P = 0.036), higher potassium (crude OR: 2.36; 95% CI: 1.31–4.26, P = 0.004), higher urea (crude OR: 1.23; 95% CI: 1.11–1.38, P = 0.000) and were associated with increased risk of symptomatic bradyarrhythmias on univariate analysis. However, these variables were not statistically significant on multivariate logistic regression analysis.
Table 5.
Univariate logistic regression analyses divided into presence or absence of β-blocker arms.
Variables | Presence of β-blocker | Absence of β-blocker | ||||
Crude OR | (95% CI) | P value | Crude OR | (95% CI) | P value | |
Age | 1.07 | (1.03–1.11) | 0.000 | 1.02 | (0.99–1.05) | 0.158 |
Male | 1.67 | (0.76–3.63) | 0.207 | 0.71 | (0.32–1.58) | 0.399 |
Malay versus non–Malayπ | 2.05 | (0.96–4.38) | 0.064 | 1.95 | (0.92–4.16) | 0.083 |
BMI, kg/m2 | 1.00 | (0.92–1.09) | 0.949 | 0.81 | (0.71–0.92) | 0.001 |
Cigarette smoking (current/former) | 0.71 | (0.21–2.40) | 0.586 | 0.85 | (0.31–2.29) | 0.742 |
Hypertension | 5.60 | (1.51–20.72) | 0.010 | 1.15 | (0.54–2.46) | 0.715 |
Diabetes mellitus | 1.87 | (0.89–3.91) | 0.098 | 0.84 | (0.40–1.77) | 0.641 |
Obstructive airway disease | 2.11 | (0.19–23.92) | 0.547 | 0.37 | (0.07–17.3) | 0.175 |
Prior CVA | 1.58 | (0.26–9.85) | 0.622 | 3.21 | (0.60–17.3) | 0.175 |
Concomitant use of rate–controlling drugs¶ | 2.25 | (0.63–7.92) | 0.209 | 9.55 | (1.13–80.41) | 0.038 |
LVEF | 1.02 | (0.98–1.06) | 0.307 | 0.99 | (0.95–1.03) | 0.557 |
FBS | 0.99 | (0.90–1.11) | 0.970 | 0.99 | (0.91–1.07) | 0.766 |
Sodium | 0.04 | (0.81–0.99) | 0.036 | 1.00 | (0.92–1.09) | 0.985 |
Potassium, | 2.36 | (1.31–4.26) | 0.004 | 0.03 | (0.97–3.31) | 0.063 |
Urea | 1.23 | (1.11–1.38) | 0.000 | 1.09 | (0.99–1.20) | 0.062 |
eGFR | 0.97 | (0.96–0.98) | 0.000 | 0.99 | (0.97–0.99) | 0.023 |
ALT | 1.01 | (0.99–1.02) | 0.181 | 1.00 | (0.99–1.01) | 0.267 |
TC | 0.76 | (0.52–1.09) | 0.138 | 0.65 | (0.40–1.07) | 0.090 |
π Other ethnicity such as Chinese, Indian, Indigenous (Orang Asli) and non-Malaysians; ¶rate-controlling drugs (viz. digoxin, verapamil, diltiazem, amiodarone or ivabradine). ALT: alanine aminotransferase; BMI: body mass index; CVA: cerebro-vascular accident; eGFR: estimated glomerular filtration rate; FBG: fasting blood glucose; LVEF: left ventricular ejection fraction; TC: total cholesterol; OR: odds ratio.
Table 6.
Multivariate logistic regression analyses divided into presence or absence of β-blocker arms.
Covariate | Presence of β-blocker | Absence of β-blocker | ||||
Adjusted OR | (95% CI) | P value | Adjusted OR | (95% CI) | P value | |
Age | 1.09 | (1.03–1.15) | 0.003 | 1.03 | (0.98–1.09) | 0.232 |
Male | 1.92 | (0.64–5.71) | 0.243 | 0.74 | (0.23–2.41) | 0.618 |
Hypertension | 4.44 | (0.80–24.67) | 0.088 | 0.62 | (0.15–2.56) | 0.624 |
Diabetes mellitus | 1.21 | (0.43–3.33) | 0.718 | 0.93 | (0.31–2.79) | 0.891 |
BMI, kg/m2 | 1.05 | (0.93–1.17) | 0.442 | 0.82 | (0.70–0.95) | 0.009 |
Malay versus non-Malayπ | 2.99 | (0.94–9.49) | 0.063 | 3.04 | (0.87–10.62) | 0.082 |
Concomitant use of rate-controlling drugs ¶ | 1.25 | (0.29–9.58) | 0.824 | 6.15 | (0.42–90.76) | 0.186 |
Sodium, mmol/L | 0.93 | (0.81–1.07) | 0.287 | 1.04 | (0.93–1.16) | 0.515 |
Potassium, mmol/L | 1.64 | (0.75–3.58) | 0.212 | 1.02 | (0.91–1.14) | 0.711 |
eGFR, mL/min per 1.73m2 | 0.98 | (0.96–1.00) | 0.103 | 0.99 | (0.97–1.01) | 0.328 |
π Other ethnicity such as Chinese, Indian, Indigenous (Orang Asli) and non-Malaysians; ¶rate-controlling drugs (viz. digoxin, verapamil, diltiazem, amiodarone or ivabradine). BMI: body mass index; eGFR: estimated glomerular filtration rate.
On univariate analysis, a statistically significant inverse association was observed for eGFR and symptomatic bradyarrhythmias in both ‘presence of β-blocker’ (crude OR: 0.97; 95% CI: 0.96–0.98, P = 0.000) and ‘absence of β-blocker’ (crude OR: 0.99; 95% CI: 0.97–0.99, P = 0.023) arms. However, using multivariate logistic regression and controlling for other variables, eGFR was not statistically significant associated with symptomatic bradyarrhythmias in the final model of both ‘presence of β-blockers’ (adjusted OR: 0.98; 95% CI: 0.96–0.98, P = 0.103) and ‘absence of β-blockers’ (adjusted OR: 0.99; 95% CI: 0.97–1.01, P = 0.328). Variables such as urea and creatinine had multicollinearity with the eGFR were not included in the final logistic regression model.
Age was statistically significant as a predictor of symptomatic bradyarrhythmias in patients ‘on β-blockers’ as compared to patients ‘not on β-blockers’ in univariate analysis (crude OR: 1.07; 95% CI: 1.03–1.11, P = 0.000 vs. crude OR: 1.02; 95% CI: 0.99–1.05, P = 0.158, respectively) and multivariate analyses (adjusted OR: 1.09; 95% CI: 1.03–1.15, P = 0.003 vs. adjusted OR: 1.03; 95% CI: 0.98–1.09, P = 0.232, respectively).
In the ‘absence of β-blocker’, concomitant use of rate-controlling drugs (crude OR: 9.55; 95% CI: 1.13–80.41, P = 0.038) was associated with increased risk of symptomatic bradyarrhythmias on univariate analysis. However, after controlling for other variables, ‘concomitant use of rate-controlling drugs' was numerically higher but not statistically significant in association with symptomatic bradyarrhythmias regardless of presence (adjusted OR: 1.25, 95% CI: 0.29–9.58, P = 0.824) or absence (adjusted OR: 6.15, 95% CI: 0.42–90.8, P = 0.186) of β-blockers. In addition, a statistically significant inverse association was observed for BMI and symptomatic bradyarrhythmias on univariate (crude OR: 0.81; 95% CI: 0.71–0.92, P = 0.001) and multivariate analysis (adjusted OR: 0.82; 95% CI: 0.70– 0.95, P = 0.009) in the “absence of β-blocker arm”.
Table 7 shows the outcomes of symptomatic bradyarrhythmias in relation to different types of β-blockers. Metoprolol and atenolol were most frequently used β-blocker observed in our study in association with bradyarrhythmias. The majority of symptomatic bradyarrhythmias were reversible following cessation of β-blockers or other causative factors such as rate-control drugs.
Table 7.
Outcome of 57 patients with symptomatic bradyarrhythmias on β-blockers.
Number of patient on different types of β-blockers | Total | ||||||||
Atenolol | Metoprolol | Bisoprolol | Carvedilol | ||||||
R | IR | R | IR | R | IR | R | IR | ||
Sinus bradycardia | 8 | 0 | 7 | 0 | 4 | 0 | 2 | 0 | 21 |
Junctional bradycardia | 5 | 0 | 4 | 2 | 1 | 0 | 0 | 0 | 12 |
Third degree AV block | 2 | 1 | 1 | 5 | 2 | 0 | 0 | 1 | 12 |
Sick sinus syndrome | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 |
Mobitz type 1 AV block | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Mobitz type 2 AV block | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 |
2: 1 AV block | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
First degree heart block | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
Others | 0 | 0 | 3 | 1 | 1 | 0 | 0 | 0 | 5 |
Total | 18 | 1 | 17 | 9 | 9 | 0 | 2 | 1 | 57 |
R (reversible): symptomatic bradyarrhythmias reversed to normal heart rate (> 60 beats/min) after cessation of β-blockers or rate-controlling drugs. IR (irreversible): symptomatic bradyarrhythmias persisted and required permanent pacemaker implantation; Others: Left bundle branch block with atrial fibrillation, 3:1 AV block, atrial flutter with junctional escape beats.
Among the cohorts, we performed subgroup exploratory analysis on the symptomatic bradyarrhythmias arm (cases) to look into the ECG diagnoses and reversibility of bradyarrhythmias as shown in Figure 1. Of the 108 cases presenting with symptomatic bradyarrhythmias, 69 patients (63.9%) with symptomatic bradyarrhythmias have shown reversibility that required no further intervention, and 39 (36.1%) were irreversible that subsequetly required permanent pacemakers. Of the 57 patients on β-blocker and symptomatic bradyarrhythmias, 30 (52.6%) patient's ECG normalized following discontinuation of β-blockers or removal of the causative factors, 16 (28.1%) required temporary pacemaker but subsequently normalized and 11 (19.3%) were irreversible required permanent pacemaker implantation. Our exploratory analysis suggests that the most common reversible electrocardiographic pattern observed in patients on β-blockers was sinus bradycardia. Serious complications (in-hospital death) due to symptomatic bradyarrhythmias were not encountered in our cohort. There was one in-hospital death due to septicaemic shock in the bradyarrhythmias arm and the cause of death was not related to bradyarrhythmias.
Outcomes of 108 patients with symptomatic bradyarrhythmias (cases) divided according to ECG diagnoses and the ‘presence’ or ‘absence’ of β-blocker use.
Reversible: symptomatic bradyarrhythmias reversed to normal heart rate (> 60 beats/min) after cessation of β-blockers or rate-controlling drugs. Irreversible: symptomatic bradyarrhythmias persisted and required permanent pacemaker implantation. Others: Left bundle branch block with atrial fibrillation, 3: 1 atrioventricular block, atrial flutter with junctional escape beats.
4. Discussion
We conducted a literature search using Pubmed, Cochrane library, Ovid MEDLINE, Scopus and Google Scholar (until March 2016) did not return any studies related to the predictors of bradyarrhythmias in patients on β-blockers. Our study is unique that we identified hospitalized patients diagnosed with symptomatic bradyarrhythmias in relation to the presence and absence of β-blockers, which enables us to identify the potential risk factors in a selected cohort. Our preliminary results showed that older age was statistically significant as a predictor of symptomatic bradyarrhythmias in patients on β-blockers than those without β-blockers by univariate and multivariate regression analyses. In our cohort, the mean age of patients with symptomatic bradyarrhythmias belonged to the older age group (64.4 ± 13.4 years). Although we could not identify a cut-off point (knot) of age to predict symptomatic bradyarrhythmias in our statistic analysis, we think that our finding would be relevant in clinical setting. Nevertheless, our study population was small and restricted to hospitalized patients. Therefore, it is impossible to ascertain whether β-blockers was underused in an elderly community population with indication for β-blocker, or whether it is appropriately used and more carefully titrated among these elderly patients.
Aging is associated with electrical and structural changes of the myocardium; the response to catecholamines is also reduced and the baroreceptor reflex activity is blunted. These aspects conceivably affect the response to antiarrhythmic drugs such as β-blockers. Furthermore, age-related changes in pharmacokinetics and pharmacodynamics make the elderly vulnerable to the development of ADR., Previous cross sectional and retrospective studies shown that the use of β-blockers have been associated with ADR in older patients. A retrospective study of ADR-related hospitalizations of older veterans showed that bradycardia secondary to beta-blockers and digoxin was the most common cause of preventable hospitalization. Another study found that serious ADR were developed by 4% of hospitalized patients taking cardiovascular drugs. Those at highest risk were older, were receiving multiple drug therapy and had higher urea levels. Warfarin and beta-blockers were the drugs causing the largest number of adverse effects. In a cross sectional study of ADR-related hospitalization, found that the elderly and the poor are most affected by ADR. The study found that β-blockers consisted of 7.9% of the major therapeutic classes implicated in ADR. Nevertheless, the common belief of β-blockers intolerance in the older population was not supported by RCTs. The evidence from RCTs indicates that β-blockers can be used safely and successfully in most elderly patients with CHF.,,[25] Further evidence comes from the SENIORS trial which was specifically designed to investigate the effects of beta-blockade (Nebivolol) in elderly CHF patients (mean age 76 years). Bradycardia was reported as an adverse event in 118/1067 (11%) patients in β-blockers arm versus 28/1061 (2.6%) patients in placebo arm. However, β-blockers discontinuation rate due to intolerance was only 2.2% as compared to placebo (0.8%). It is sensible to anticipate the pharmacological differences between younger and older patients. With increasing age, renal function (or more precisely GFR) declines steadily which affect the clearance of renally metabolized medications. Thus, additional dosage adjustment is necessary in the elderly especially if the drug elimination is via kidney. In addition, drug-disease interactions or drug-drug interaction may occur because of polypharmacy in older population. As a result, this may unmask the underlying intrinsic disease of the sinus node or AV node causing pacemaking dysfunction that manifest as bradycardia that warrant further studies.
We found an inverse association between eGFR and symptomatic bradyarrhythmias in patients with and without β-blockers in univariate analysis. However, eGFR was not a predictor of symptomatic bradyarrhythmias on multivariate analysis regardless of presence or absence of β-blockers. In other words, lower eGFR was identified as a risk factor (or, higher eGFR was identified as a protective factor) of symptomatic bradyarrhythmias on univariate analysis. A possible explanation is the alteration of pharmacokinetics and pharmacodynamics of β-blockers in renal insufficiency. It is important to know that lipophilic β-blockers such as metoprolol and propranolol are metabolized in the liver whereas hydrophilic β-blockers such as atenolol are almost exclusively eliminated in the kidneys. For this reason, the half life of hydrophilic β-blockers is significantly prolonged due to unfavorable excretion in renal insufficiency. Dose has to be adjusted according to renal function in the case of atenolol, sotalol and acebutolol. Drugs like bisoprolol, betaxolol and pindolol have both hepatic and renal clearance. Another possible explanation for symptomatic bradyarrhythmias is the metabolic and electrolyte disturbance in renal insufficiency. Our study also showed that higher urea, potassium and lower sodium were significantly associated with symptomatic bradyarrhythmias in patients with β-blockers versus those without β-blockers on univariate analysis. It has been reported that electrolyte abnormalities such as hyperkalemia and hypercalcemia could responsible for heart block in chronic renal failure.
A recent meta-analysis by Badve et al. included six placebo-controlled heart failure trials of patients with CKD stages 3 to 5 (eGFR ≤ 60 mL/min per 1.73 m2) demonstrated that β-blockers (carvedilol, metoprolol, bisoprolol, nebivolol and acebutolol) reduce mortality. However, the benefit of β-blockers came at a price of increased risk of bradycardia [risk ratio (RR): 4.92, 95% CI: 3.20–7.55]. Similarly, other studies on the use of β-blockers in patients with renal insufficiency demonstrated marginally significant increase in bradycardia and higher rate of discontinuation due to adverse event such as hypotension and bradycardia.
Regardless of presence or absence β-blockers, our study showed that ‘concomitant use of rate-controlling drugs’ has numerically higher adjusted OR but not statistically significant in association with symptomatic bradyarrhythmias estimated by multivariate regression analyses. It has been shown that β-blockers and concomitant use of other drugs such as non-dihydropyridine calcium channel antagonists (diltiazem and verapamil) were the cause of acquired complete AV block causing bradycardia in clinical practice. A study by David et al aimed to determine the prognosis of drug induced-AV block found that AV block is commonly “related to drugs” but rarely “caused by drugs”. Only 15% of patients who had second or third degree AV block during therapy with β-blockers, verapamil, or diltiazem was “truly caused by drugs”. A study by Lee, et al. found that β-blockers were the most common drugs associated with drug-related bradycardia (DRB). In this study, drug discontinuation was followed by resolution of bradycardia in 60% of patients. In 23% of the cases, bradycardia persisted despite drug withdrawal, and warrant permanent pacemaker implantation. The results of our analysis showed that the majority (52.6%) of symptomatic bradyarrhythmias on β-blockers were reversible without the need of permanent pacemaker. Our study suggests that sinus bradycardia and junctional bradycardia were the most common reversible electrocardiographic pattern in association with β-blockers. Similar ECG diagnosis was reported in the above mentioned DRB study that sinus bradycardia and sinus bradycardia with junctional escape beats were most frequently observed. Notably, our study did not report any in-hospital death as a result of symptomatic bradyarrhythmias. The contributing factors towards the irreversibility of bradyarrhythmias were beyond the scope of our study. We were intrigued by the finding of higher BMI as a risk factor of symptomatic bradyarrhythmias in the multivarate analysis. This finding should be interpreted with caution because it may be related to differences in the patients who were enrolled, or it may simply represent the play of chance in statistical analyses that needs further study.
It is well-established that the survival benefit of β-blockers outweighs the side-effects risk as proven by observational, prospective and RCTs and its use is highly recommended by the CPG especially in treating heart failure and IHD.,,, These results should alleviate concerns in prescribing β-blockers particularly in patients with heart failure where the absolute survival benefits of β-blockers are most pronounced.,[25] However, medication could be a double-edge sword. The result of our study does not intend to refute the benefit of β-blockers but has its clinical importance. The ability to predict potential bradyarrhythmias occurrence may be beneficial and may warrant managing patients on β-blockers more cautiously. Meanwhile, careful evaluation and constant monitoring are necessary when prescribing β-blockers to prevent ADR. ADR is an important cause of preventable morbidity with serious economic implications. Hence, special attention should be given to their prevention.,,,[25] Guidelines and experts recommend that β-blockers should be prescribed at low initial doses and gradually titrated every two weeks to research validated targets or the maximally tolerated dose.,, Patients should be instructed about the most common adverse effects (bradyarrhythmias, hypotension or worsening heart failure) which can arise in any patient if the dosage of β-blocker is too high or escalated too rapidly.
4.1. Limitation
Unlike RCTs, the authors recognize the limitation inherent in this retrospective observational study, and without RCTs we can never rule out unidentified confounders. We had difficulty in selecting suitable cases and our definition of symptomatic bradyarrhythmias was not stringent. It is because bradyarrhythmias vary in their types and nature and it is therefore difficult to decide which cases should be included. We dealt with this by recruiting all types of bradyarrhythmias with or without β-blockers use. Similar for controls, we recruited patients of similar risk profiles with the presence or absence of β-blockers use. Despite our effort to minimize sampling bias, we cannot be sure that controls in our study ideally represent the source population to which the cases belong.
This study was constrained by small number of cases because the diagnosis of symptomatic bradyarrhythmias was rare. The small sample size was reflected in wide confidence intervals. Our focus on subjects in a single center (Johor Bahru) limits the extrapolation of the findings to entire population. However, because there is no other identical study on this topic as yet, our preliminary result may provide a basis for future study.
We recruited patients on different types of the β-blockers with comparable maximum daily dose of β-blockers in cases and controls. However, the type of β-blockers was self-reported and subjected to recall bias. The usage of different brands of generic and original beta blockers in our cohort may account for the differences in the active drugs among groups, and may potentially affect the outcomes.
Furthermore, we draw generalized conclusion with regards to the outcomes of all types of bradyarrhythmias in association with the use of different β-blockers. Other types of β-blockers such as nevibolol, sotalol, esmolol, pindolol and nadolol were not commonly prescribed in our practice and were not included in the analyses. The outcome results could be different if we include different type of β-blockers with different pharmacokinetic and pharmacodynamic properties. Obviously, further multicenter study with larger cohorts for the identification of cases, and lesser probability of referral bias to a single center is required to confirm the validity of these findings.
4.2. Strength
The main strength of this study is the design of a hospital-based case-control study that allowed us to identify risk factors of symptomatic bradyarrhythmias in association with the use of β-blockers. Unlike restricted populations in randomized control trials which tend to exclude high risk patients such as elderly and CKD patients. We believe our study is complementary to the existing RCTs and provided useful adjunctive information on the usage of β-blockers.
4.3. Conclusions
Our preliminary results showed that older age was statistically significant as a predictor of symptomatic bradyarrhythmias in patients on β-blockers than those without β-blockers. Majority of patients with symptomatic bradyarrhythmias on β-blockers were reversible without the need of permanent pacemaker implantation. The results should be intepreted with caution because of the small sample size and larger studies are required to confirm or refute these findings.
Acknowledgments
The authors would like to thank the Director General of Health Malaysia for permission to publish this research paper. We particularly thank pharmacists and nurses for invaluable help in checking the types and dosages of β-blockers, verifying patients' information and extracting the data from the medical records.
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Articles from Journal of Geriatric Cardiology : JGC are provided here courtesy of Institute of Geriatric Cardiology, Chinese PLA General Hospital
An arrhythmia is a condition in which the heart beats too quickly, too slowly, or irregularly.
In many cases, the arrhythmia may not be serious or require any treatment at all. However, if your doctor finds that the arrhythmia could lead to more serious heart problems, they may prescribe medication.
Several types of medication can help control or resolve an arrhythmia. The type that’s right for you depends on the kind of arrhythmia you have.
Here’s what to know about drugs that treat arrhythmia.
Antiarrhythmic drugs may be prescribed if you have tachycardia (fast heart rate) or premature or extra heartbeats. These medications work to correct the rhythm of your heart. They restore a normal heart rhythm by changing the electrical current that makes your heart beat.
Most antiarrhythmic drugs come in pill form and are typically used long-term. In emergencies, some can be given intravenously. The most common medications in this class are:
- amiodarone (Cordarone, Pacerone)
- flecainide (Tambocor)
- ibutilide (Corvert), which can only be given through IV
- lidocaine (Xylocaine), which can only be given through IV
- procainamide (Procan, Procanbid)
- propafenone (Rythmol)
- quinidine (many brand names)
- tocainide (Tonocarid)
While these medications can help correct an arrhythmia, there’s also a risk that they can cause the arrhythmia to occur again or more often. This is called a proarrhythmia. If you develop a proarrhythmia while taking an antiarrhythmic drug, call your doctor right away.
If you have angina (chest pain), high or low blood pressure, and an arrhythmia, your doctor may prescribe a calcium channel blocker. These drugs dilate your blood vessels. This allows more blood to flow to the heart, which helps ease chest pain and decrease blood pressure.
These drugs can also slow your heart rate. A reduced heart rate and lowered blood pressure reduce the strain on your heart and reduce your risk of an arrhythmia.
Most calcium channel blockers come in pill form, but some are also available in intravenous (IV) form. Calcium channel blockers are for long-term use.
Examples of common calcium channel blockers include:
- amlodipine (Norvasc)
- diltiazem (Cardizem, Tiazac)
- felodipine
- isradipine
- nicardipine (Cardene SR)
- nifedipine (Procardia)
- nisoldipine (Sular)
- verapamil (Calan, Verelan, Covera-HS)
The side effects of these medications vary. Some people have tachycardia, dizziness, constipation, and headaches. Other people more serious side effects include rash or swelling in the legs and feet.
If you’ve been diagnosed with tachycardia, your doctor may prescribe a beta-blocker.
Beta-blockers stop the action of the hormone adrenaline. This can relieve your tachycardia by slowing your heart rate. It can also lower your blood pressure and decrease the stress on your heart. Examples of beta blockers include:
- acebutolol (Sectral)
- atenolol (Tenormin)
- bisoprolol (Zebeta)
- metoprolol (Lopressor, Toprol-XL)
- nadolol (Corgard)
- propranolol (Inderal LA, InnoPran XL)
The side effects of beta-blockers include tiredness, cold hands, and headache. Sometimes these medications affect your digestive system as well. Some people report stomach issues, constipation, or diarrhea.
An anticoagulant is a blood-thinning medication. Your doctor may prescribe an anticoagulant if your arrhythmia puts you at risk of clots or stroke caused by a clot.
For some people, an abnormal heart rhythm changes how the blood flows through their system. For instance, atrial fibrillation may cause blood to pool in the heart, which may result in blood clots.
Anticoagulants don’t fix your heart rhythm problem. They only help reduce the risk of blood clots caused by certain arrhythmias.
Warfarin (Coumadin) is one of the most common anticoagulants. However, non-vitamin K oral anticoagulants (NOACs) are now recommended over warfarin unless you have moderate to severe mitral stenosis or an artificial heart valve. NOACs include:
- dabigatran (Pradaxa)
- rivaroxaban (Xarelto)
- apixaban (Eliquis)
- edoxaban (Savaysa)
Anticoagulants are effective, but they can also make your body less able to stop bleeding. For this reason, you should watch for any signs of internal bleeding, such as bloody stool, multiple bruises, and vomit that looks like coffee grounds.
Your doctor may prescribe aspirin instead of warfarin if they find that you have a lower risk of a blood clot. Aspirin is not as powerful of a blood thinner as warfarin is. However, it has a lower risk of causing bleeding.
Your heart is a very important organ. To stay safe while taking your medications, try these tips:
- work with your doctor to understand the medications they prescribed for you
- take your medications only as directed
- tell your doctor about all other medical conditions you have and medications you take
- call your doctor right away if you notice anything abnormal or if you have serious side effects
Q:
I take several heart medications. How can I manage them?
A:
It’s important to keep your drugs organized so you don’t take too much or too little medication. These tips can help:
• Use a pill dispenser to track when you should take a pill.
• Fill all of your prescriptions at one pharmacy to make getting refills easier.
• Keep a drug list to record all of the medications you take.
Published online 2012 Feb. doi: 10.2174/157340312801215764
PMID: 22845818
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Abstract
Beta-Blockers [BB] have been used extensively in the last 40 years after acute myocardial infarction [AMI] as part of therapy and in secondary prevention. The evidence for “routine” therapy with beta-blocker use post AMI rests largely on results of trials conducted over 25 years ago. However, there remains no clear recommendation regarding the appropriate duration of treatment with BBs in post AMI patients with normal left ventricular ejection fraction [LVEF] who are not experiencing angina, or who require BB for hypertension or dysrhythmia. Based on the latest ACC/AHA guidelines, BBs are recommended for early use in the setting of AMI, except in patients who are at low risk and then indefinitely as secondary prevention after AMI. This recommendation was downgraded to class IIa in low risk patients and the updated 2007 ACC/AHA guidelines suggest that the rationale for BB for secondary prevention is from limited data derived from extrapolations of chronic angina and heart failure trials. In this review, we examine the key trials that have shaped the current guidelines and recommendations. In addition, we attempt to answer the question of the duration of BB use in patients with preserved LVEF after acute MI, as well as which subgroups of patients benefits most from post AMI use of beta blockers.
Keywords: Acute myocardial infarction, Beta Blockers, Secondary prevention.
INTRODUCTION
The current guidelines on secondary prevention in patients status post acute myocardial infarction (AMI) recommend starting Beta Blockers (BB’s) for long term use (indefinite) in all patients (class I) []. These recommendations are based on several major trials including the Beta Blocker Heart Attack Trial (BHAT), the Norwegian Metoprolol Trial, Stockholm Metoprolol Trial, Cooperative Cardiovascular Project, Goteborg Trial, and a meta-analysis by Freemantle et al. [-]. The 2004 ACC/AHA guidelines changed this recommendation to class IIa in low risk patients [], while the updated 2007 ACC/AHA guidelines believe that the rationale for BBs for secondary prevention is from limited data derived from extrapolations of chronic angina and heart failure trials [-]. The paucity of data may suggest the need to reevaluate recommendations regarding the duration of BB use in post AMI patients with normal left ventricular systolic function (LVSF). In this review, we examine the key trials that have shaped the current guidelines and recommendations. We review the immediate (days-months) and long term (years) effects of BBs on mortality and morbidity in patients after an AMI both in the pre and post-thrombolytic era. We will address the question: on which subgroups of patients, or upon which complications of acute myocardial infarction do BBs confer the most benefit? In addition, we will attempt to answer the question of the appropriate duration of BB use in patients with preserved LVSF after acute MI.
Beta-Blockers have been used extensively in the last 40 years after (AMI) as part of primary therapy and in secondary prevention. They are employed for multiple indications such as hypertension [], perioperative cardioprotection [-], angina [] post cardiac surgery atrial fibrillation prevention [-] and arrhythmias. Early BB therapy has been recommended as part of the emergency treatment of suspected AMI, especially if the patient is tachycardic or hypertensive. Current recommendations for the use of BB’s in AMI are found in the 2004 Task force and 2004/2007 ACC/AHA STEMI guidelines. The evidence for “routine” therapy with beta-blockers post AMI rests largely on results of the trials conducted over 25 years ago.
Despite these recommendations, there seems to be no clear consensus among cardiologists regarding the appropriate duration of treatment with BBs in post AMI patients with normal LVEF who are not experiencing angina, or who require BB for hypertension or dysrhythmia. Knowledge of the appropriate duration of treatment is relevant because of adverse effects of BB, including bradycardia, hypotension, bronchospasm, fatigue, reduced libido, depression, new onset diabetes and the additional medication burden.
Beta blockers reduce myocardial workload, and thus oxygen demand, via a reduction in heart rate and blood pressure [-]. They reduce catecholamine levels [], decrease myocardial ischemia and limit infarct size, and may prevent the development of definite infarction in acute coronary syndrome (ACS) patients [-]. Early use of BBs in AMI has been shown to reduce the incidence of supraventricular and malignant ventricular arrhythmias, reduce the use of other anti-arrhythmic medications [,-], decrease chest pain symptoms [], and decrease sudden cardiac death and early and late re-infarction [,-].
Current recommendations regarding the use of BBs in the management of AMI as found in the ACC/AHA guidelines are highlighted here: BBs are currently recommended as long term-treatment for chronic, stable ischemic heart disease to control ischemia, prevent infarction and improve survival []. BBs are recommended to be used indefinitely in patients with decreased LVEF after AMI [] and in patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV [-]. They are recommended for early use in the setting of AMI, except in patients who are at low risk (normal or near-normal LVEF, who have been successfully reperfused, or in the absence of significant ventricular arrhythmias). Listed contraindications include severe LV dysfunction. These recommendations are based on several large trials including ISIS-1, MIAMI, TIMI-IIb and GUSTO-I, all of which evaluated the effect of beta blockers during the acute phase of MI [-,-]. The benefits of routine early intravenous (IV) use are felt to be less impressive based on the data obtained in the reperfusion era.
SHORT TERM BENEFIT IN THE PRETHROMBOLYTIC ERA
The Goteborg trial [] was one of the first randomized, double-blinded trials to demonstrate the beneficial effect of BBs on survival during the early phase of AMI. The protocol randomized 1,395 patients to metoprolol vs. placebo. Intravenous metoprolol was initially given followed by oral metoprolol. The authors found that patients treated within 12 hours of onset of ischemic pain had lower LDH values, (a measure of infarct size) and a 16% decrease in index infarctions. In the subsequent 90 days, there was a 36% reduction in mortality, 35% reduction in late MI and a decrease in ventricular fibrillation (VF) in the metoprolol-treated group. The reduction in mortality was similar in all defined subgroups. All patients were placed on open treatment with metoprolol after 90 days of double-blinded therapy. The mortality difference between the two groups was maintained at 1 year. The authors recommended the use of metoprolol during the early phase of AMI followed by long-term treatment, without specifying the actual duration. They only report one year follow-up, so benefit beyond that is only speculative.
The MIAMI trial (Metoprolol in acute myocardial infarction) [] was the next major randomized double-blind placebo-controlled trial designed to test the benefit of BBs in suspected AMI. It randomized 5,778 patients to IV metoprolol or placebo within 24h of symptom onset, followed by oral treatment for 15 days. Overall there was no statistical difference in mortality between the treatment and placebo groups. In a retrospective analysis, the “high risk” patients demonstrated a 29% decrease in mortality rate. The authors suggested interpreting the P-value of 0.033 with caution as this analysis was made retrospectively. There was a non-significant decrease in the number of episodes of VF and re-infarction. The authors did report a significant decrease in development of definite infarction and reduction in tachyarrythmias with metoprolol therapy. The beneficial effect of metoprolol was limited to patients treated within 7 hours of symptom onset. The authors noted that the overall mortality rate was lower than predicted, and concluded that early institution of metoprolol did not reduce mortality. They suggested that this was due to selection bias.
A comprehensive analysis by Yusuf et al. [] followed the MIAMI and Goteborg trials and examined mortality and morbidity rates in randomized trials of beta-blockers after AMI. They found that short term treatment demonstrated a slight, non-significant benefit in mortality (3.4% vs. 3.6%, treatment vs. control), and no effect on ventricular arrhythmias or infarct size. The analysis suggested that because many trials used only oral BB, or did not initiate therapy until up to 72 hours after onset of chest pain, episodes of ventricular arrhythmias, which commonly occur in the early hours of AMI, may have been “missed”. The study did show significant reductions in cardiac enzyme release, chest pain and development of full MI in “threatened infarction” in patients treated within the first few hours of the onset of pain. It is important to note that these reductions were seen in only 12 of the 27 trials reviewed.
The First International Study of Infarct Survival-ISIS-1 [] randomized 16,027 patients to atenolol given IV immediately, followed by oral administration for 7 days. The study showed a 15% relative risk reduction in vascular mortality during the treatment period, but benefit was limited to administration during days 0-1. The study also showed significantly lower overall vascular mortality at one year, assumed to be due to the more likely use of BBs at discharge in the atenolol group [35% vs. 25% in controls]. The benefit was lost with follow-up beyond one year. More power armor mods. Treatment also resulted in a significant increase in use of inotropic agents, non-significant increases in complete heart block, non-fatal re-infarctions and cardiac arrests, and no effect on the magnitude of cardiac enzyme release. The study did suggest that early IV treatment might produce ~15% reduction in the odds of cardiac arrest and an 18% reduction in the odds of early re-infarction. The authors concluded that the early gains of net decrease in death, cardiac arrest and re-infarction would persist after day 7 of treatment. They recommended to view these findings with caution, because they believed that BBs were prescribed for lower-risk patients. The ISIS-I study was not able to confirm the findings of the MIAMI trial, where benefit was seen retrospectively in “high risk” patients. The ISIS authors suggest that the findings “might be generalizable” but not to those at high risk [].
BETA BLOCKER USE WITH THROMBOLYTIC THERAPY
Trials addressing the use of early IV beta blockade were conducted after the widespread use of reperfusion therapy began. The first major study of AMI in the thrombolytic era which also addressed early use of BBs was the Thrombolysis in Myocardial Infarction (TIMI II-B) study []. It assessed the effects of immediate versus deferred BB therapy in patients receiving IV recombinant tissue-type plasminogen activator. The hypothesis tested was based on the rationale that with thrombolytic treatment, the highly vulnerable period for SCD may start earlier than the conventional period of 6-12 weeks in the non-thrombolytic experience. The study randomized 1,434 patients to immediate IV metoprolol followed by oral administration, or to deferred therapy where oral administration began on day 6. The authors found that immediate beta-blockade produced no improvement in LVEF, nor reduced mortality (in both invasive and non-invasive treatment arms) at hospital discharge. The authors believed that BB treatment did not change LVEF sufficiently to be detected (the primary end point) since patients with depressed LVEF were excluded. In fact, because of numerous exclusion criteria, the randomized population was a low risk group. In the secondary endpoints analysis, the study showed that early administration of BBs resulted in a lower incidence of re-infarction (2.7% vs. 5.1%, p=0.02) and recurrent chest pain (18.8% vs. 24.1%, p<0.02) at 6 days versus deferred therapy, but no difference at one year (8.6% vs. 9.6%, p=0.44) In conclusion, immediate BB use was recommended for prevention of ischemia and re-infarction during the first week following thrombolytic therapy, but offered no benefit over late administration. Mean discharge LVEF in both groups was 50% and was unchanged at one year. Again, later follow-up was not reported, and in the absence of a non BB-treated cohort, benefit beyond one year remains at best speculative.
Pfisterer and colleagues, in the pre-specified post-hoc analysis of the GUSTO-I trial, reported the results of a non-randomized observational study, examining 30-day mortality of fibrinolytic-treated patients with ST-elevation MI who received any atenolol (IV, oral or both) or no atenolol [] Use of any atenolol conferred a 5-fold lower mortality risk than if no atenolol had been given, but the majority of the benefit was limited to oral use only. Overall, use of atenolol in GUSTO-I was associated with decreased mortality, stroke, shock and arrhythmias, but increased recurrent ischemia and re-infarction. The authors reported that interpretation of this data is confounded by the fact that atenolol-treated patients were less ill at presentation and may have already had preservation of LV function. The authors concluded that IV atenolol adds only limited value to early oral atenolol and recommended to begin oral atenolol once the patient is clinically stable.
A meta-analysis by Freemantle et al published in 1999 reported on 82 randomized trials which examined the effects of BBs on all cause mortality with both short and long term treatment []. Review of the 51 short term trials involving 29,260 patients showed a small and non-significant reduction in the odds of death (0.4 deaths in 100 patients). The authors concluded that short term beta blockade immediately after myocardial infarction is unlikely to be of major benefit unless treatment is continued long term.
The Commit study, one of the largest trials, randomized 45,852 patients to early IV metoprolol followed by oral metoprolol or placebo within 24 hours of suspected AMI onset. Treatment was up to discharge or 4 weeks in the hospital []. This study included Killip class II and III patients (24%), who were excluded in many of the previous trials []. Approximately 50% of the patients in this study received fibrinolytic therapy, and patients scheduled for primary percutaneous coronary intervention (PCI) were excluded. The study showed that early BB therapy had no effect on the primary composite outcome of death, re-infarction or cardiac arrest, and no effect on the co-primary outcome of death alone. Treatment did reduce the risks of re-infarction by 18%, ventricular fibrillation by 17% and death due to arrhythmia by 22%. These reductions emerged gradually, beginning on day 2, but were counterbalanced by a 29% increase in death due to cardiogenic shock and a 12% increase in development of CHF. The authors believed this increase in shock was seen in high risk patients, and there was a tendency toward a net benefit in low-risk patients. They proposed that early after the onset of MI, higher-risk patients may be poorly perfused, and rapid reduction in blood pressure with beta-blocker therapy may further compromise the patients’ hemodynamics []. It was concluded that BB therapy be started only after a patient’s hemodynamic condition has stabilized.
Al-Reesi et al. (2008) revisited the data on the use of BBs in acute MI in a meta-analysis of 18 studies with a total 74,643 patients []. This review examined randomized controlled trials assessing 6-week mortality in patients receiving BB within 72 hours of acute MI. Fifteen out of the eighteen trials excluded patients with CHF. The study found no survival benefit from acute intervention with BB at 6 weeks, while a subgroup analysis after exclusion of high-risk patients (Killip class III and IV) showed a small but significant absolute risk reduction of 0.4% in short-term mortality []. The explanation offered for the lack of cardiovascular protection in the early phase post MI was that the myocardium might be stunned immediately after AMI, resulting in depressed ejection fraction, and the use of beta-blockers may worsen myocardial contractility under these conditions.
Review of the data regarding the benefits of short term use of BBs for reduction of mortality in AMI appears to be equivocal. Even when patients are segregated by risk category, the data is conflicting. Some trials (TIMI-IIB, ISIS, PAMI) [,] showed mortality reduction in low risk groups, while MIAMI [] and GUSTO-I [] showed reduction only in high risk groups. The Goteborg trial showed reduction in mortality in all groups[], and the Yusuf at al meta-analysis showed only a slight, non-significant benefit in mortality with BB therapy []. The data on reducing re-infarction and tachyarrhythmias seems to favor early BB use, as confirmed in most trials completed during both the pre-fibrinolytic and fibrinolytic eras [,-,-]. Thus, early oral BB therapy may reduce short term overall mortality (0-6 weeks) in both low and high risk patients, as well as reduce the rates of re-infarction and tachyarrythmias, but the data remains inconclusive. The data does suggest that the early use of IV BBs may result in higher risk of cardiogenic shock and death.
IS THERE A LONG TERM BENEFIT OF BETA-BLOCKER USE?
One of the earliest studies suggesting benefit of beta-blockers after AMI was the Norwegian Timolol Trial []. It was a double-blind randomized study of 1,884 patients which examined the effect of timolol administered 7-28 days after AMI, and followed patients for 12-33 months. The study was conducted primarily in low risk, “clinically stable” patients. The study employed an “intention-to-treat” analysis. The authors found that use of timolol resulted in a 39.4% reduction in mortality, a 44.6 % reduction in sudden-death, and a 28.4% reduction in re-infarction rates. The mortality curves continued to diverge up to 30 months, after which the curves became parallel. The authors report that after 24 months the number of at risk patients was too small to derive conclusions with respect to mortality, and report a negligible difference between the two curves for re-infarction after six months. These findings were similar to those in the American beta-blocker Heart Attack Trial (BHAT) [], the Goteborg Metoprolol Trial [] and the Stockholm Metoprolol Trial [].
Pedersen et al reported 6 year follow-up of the Norwegian Timolol Trial patients with severe angina, hypertension or cardiac arrhythmias treated with BBs for longer than 36 months (vs. placebo-treated patients for the same period) []. The benefit obtained during the first year was preserved and the curves continued to diverge until 72 months of follow-up. The benefit was seen in the older and high risk patients only. There was no significant difference at 72 months in low-risk patients [].
The BHAT trial followed the Norwegian Trial and was halted early due to a significant mortality reduction with BB treatment. The BHAT trial randomized 3,837 patients 5-21 days after acute MI to propranolol, a non-selective BB, or placebo with a mean follow-up of 27 months. Patients with bradycardia, CHF and prior BB treatment were excluded. Total mortality was reduced by 25%, sudden death by 28% and arteriosclerotic heart disease by 27%. The survival curves diverged for the first year, then became parallel. The benefits of propranolol were found to be similar in all risk groups. The authors note the limitation that the study was not designed to answer the question of duration of treatment with BBs after AMI, but based on the finding that the beneficial effects were most pronounced at 12-18 months, and sustained up to 39 months, the investigators recommended the use propranolol for at least 3 years.
A sub-analysis of the BHAT database by Viscoli et al assessed the mortality rates in the study population after division into low, medium and high risk groups, and by 12 months or more of treatment [] . The authors found that while propranolol therapy conferred an improvement in mortality of 43% among high risk patients, there was no evidence of long term benefit in the low risk population, calculated to be approximately 88% of the cohort. In addition, it highlighted that the overall risk reduction of 27% seen at 2 years occurred primarily in the first year, during which the risk reduction was 39%. In fact the risk reduction declined to 18% after 1 year, once adjusted for the effects of differences in the risk for death []. Overall, the authors concluded that the benefits of propranolol treatment in BHAT were confined to the highest risk patients. They also suggested that physicians and patients with an uncomplicated course after MI may want to reconsider the continued use of beta blockers beyond 1 year.
The findings of BHAT were further evaluated in a post-hoc analysis by Georghiade et al, who examined the cohorts with either Q-wave or non-Q-wave MI’s, the latter representing 17% of the BHAT population. This analysis found the cumulative mortality in the propranolol and placebo-treated non-Q wave MI groups to be 7.8 and 7.9% respectively (non-significantly different). In the Q-wave MI cohort there was a statistically significant 27% relative risk reduction in mortality compared with placebo. The authors concluded that the beneficial effects of propranolol were limited to the Q-wave MI population [].
Another analysis of BHAT by Hawkins et al, found propranolol to improve mortality in older patients []. The study examined patients aged 30-59 years vs. 60-69 years. The older group had a 33.3% reduction in mortality versus placebo, compared to an 18.9% reduction in the younger age group. In this latter group, benefit from propranolol was confined to the first 6 months, while in the older group there was a continuing separation of the curves up to 36 months.
The Stockholm Metoprolol study published in 1985 [] was a double-blind study which randomized 301 patients post MI to oral metoprolol vs. placebo and followed them up to 36 months. Patients with prior need for beta-blockade or patients in heart failure, atrial fibrillation, or with obstructive pulmonary disease or hypotension were excluded. There was a significant reduction in cardiac death in patients with a large infarct (32% vs. 12.5%), and a significant decrease in sudden death (59%) and nonfatal re-infarction rates (45%) in the metoprolol group. The curves for both sudden death and total mortality continued to diverge throughout the follow-up period. The total mortality between the two groups was not significantly different. The authors reported that the significant reduction in cardiac mortality was in patients with a large infarct or in patients over 64 years of age. This difference was mainly driven by reduction in sudden deaths. The authors concluded that therapy should be continued for at least 3 years. They do not mention the use of aspirin or ejection fraction, so applicability of this data is limited.
Yusuf et al’s review of 16 randomized trials on long term (1-3 years) prophylactic use of beta blockers after MI reported that a “crude overview” of the results suggested a moderate reduction of the absolute risk of death from 10% to about 8% []. The analysis also showed a 25% reduction in odds of re-infarction, and a 30% reduction in the odds of sudden death. The authors state that the trials reviewed were too small to identify subgroups of patients for whom treatment was advantageous. Very few studies in the review showed significant decreases in re-infarction rate, but when the data was pooled, there was a significant difference between the control and treatment groups. Yusuf et al believed that the analyses of sudden death to be unreliable, since the definition of sudden death varied from trial to trial. They conclude that only long term treatment trials demonstrated benefit in reducing mortality, which may be because more patients have been randomized to long term trials compared to short term trials as of the time of their review.
Another large meta-analysis by Olsson et al examined several long term double blind studies to determine if metoprolol reduced post-infarction mortality []. The five trials that were evaluated included the Goteborg Metoprolol trial and Stockholm Metoprolol trials described above, along with the Amsterdam Metoprolol Trial, Belfast Metoprolol trial and Lopressor Intervention Trial [-]. The pooled mortality rates were 19% lower in the metoprolol treated patients, compared with non-treated patients. Use of metoprolol showed a 40% reduction in sudden cardiac death. Mortality reduction was independent of gender, age and smoking habits, and was driven mainly by reduced sudden cardiac deaths. In review of the two figures representing the cumulative number of all deaths, it is evident that the two mortality curves separate early, with the major difference in mortality occurring during the first year. After one year, the curves became parallel. Only in the Stockholm Metoprolol trial did the curves for sudden death and cardiac mortality continue to diverge throughout the 36 months of follow-up [].
The meta-analysis by Freemantle et al included 31 long term trials involving 24,974 patients, and the analysis concluded that there was a 23% reduction in the odds of death with Beta blocker use [] The analysis looked at annual reduction in mortality across the trials. The findings suggested an annual reduction of 1.2 deaths and 0.9 re-infarctions for 100 patients treated. When looking at predictors of benefit, initiation with intravenous dose did not add additional benefit, but the authors found no reason to delay, as early initiation would lead to a greater period when benefit may be accrued from treatment. Use of BBs with intrinsic sympathomimetic activity showed a non-significant trend towards reduced benefit (OR 1.10). The meta-analysis concluded that there was no loss of benefit over time, as additional therapeutic options for treatment were introduced, particularly thrombolytic agents and aspirin. In their discussion, the authors highlighted that in their analysis, the number needed to treat to avoid one death was 42 with BBs compared to 153 and 94 with antiplatelet agents or statins, respectively. The authors suggested that beta blockers should be continued indefinitely.
The APSI trial [] which followed in 1997 attempted to explore the effect of long term treatment with BBs on mortality after acute MI in high risk patients. The study randomized 607 patients to 1 year of treatment with acebutolol or placebo, and had a median follow-up of 6 years. There was a 48% relative reduction in total mortality at 1 year. The difference in mortality was significant in the first year after which the survival curves remained parallel. Their analysis suggested that the initial benefit may remain until the fourth year. The patients’ treatments were specified and blinded only for the first year, after which there is no knowledge whether the patients were on BB or not. Thus, this study could not provide evidence about the optimal duration for beta-blocker therapy after AMI.
The trials reviewed above, both long term and short term were performed in the era before anti-platelet therapy and PCI had become routine, and the average mortality in the control population in these studies was approximately 4%, as the trials included primarily low-risk patients. In addition, these trials were representative of BB effects on patient populations under-treated by current standards. The patients in these trials were not treated as aggressively with ACE inhibitors, aspirin and statins as is recommended by current post-MI standards of care. Thus, it is difficult to assert that the albeit inconsistently positive effects of beta-blocker use found in these trials are definitively applicable in the current era of treatment.
One of the few studies to examine this issue of applicability was an analysis by Kernis et al of 2,442 patients who underwent successful primary PCI [] published in 2004. The study examined the outcome of patients treated with or without BBs in the PAMI-2, PAMI No SOS, Stent PAMI and Air PAMI trials. In these trials, the percent of the patients given BBs post-PCI ranged from 53% (Air PAMI) to 82% (PAMI-No SOS). In multivariate analysis, beta-blockers were independently associated with lower six-month mortality and Major Adverse Cardiac Events (MACE), with the benefit seen in patients with decreased LVEF (<50%) and multi-vessel coronary artery disease. The beneficial effect was NOT seen in patients with LVEF>50% and single-vessel CAD. The Kernis et al. speculated that complete and successful primary revascularization in patients with normal LVEF reduce the risk of cardiac events to a point where chronic beta-blockade becomes unnecessary. They also suggested that the presence of a selection bias favoring use of beta-blockers in healthier patients may have led to improved prognosis in BB patients overall.
An analysis of the Cadillac trial by Halkin et al, extended the findings of Kernis et al (2004) by examining the effect of IV BB administered before PCI on survival after AMI [] Pre-procedural BB were administered in 1,136 patients and withheld in the remaining 946 patients. The patients in the BB group were younger, had more hypertension and anterior infarction with depressed LVEF than patients not treated with pre-procedural beta-blocker. The 30-day mortality was significantly lower in the BB group (1.5% vs. 2.8%), but only for patients without prior BB therapy. In addition, no reduction in mortality was observed after 1 year. There were no differences in the 30-day rates of re-infarction, target vessel revascularization, or stroke. The authors concluded that patients unprotected at the time of AMI onset by long-term BB therapy would derive the greatest clinical benefit from IV BB administration before PCI, but one could reasonably conclude that these findings are limited in applicability and may not support long term use.
CONCLUSIONS
In summary, the Norwegian Timolol Trial, the BHAT and Stockholm trials [-,] all showed a reduction in mortality, sudden death, and re-infarction for up to 30-36 months, but these benefits were engendered by reductions occurring in the first year of therapy [,]. The benefit was limited to high risk patients [,], older patients [-,], and patients with large [] or Q-wave infarction [].The benefits persisted over 36 months in patients with severe angina, hypertension and arrhythmias only in the 6 year follow-up of the Norwegian trial []. The findings of the APSI trial suggested the persistence of benefit up to 4 years in high-risk patients, but the benefit developed in the first year without change over time []. Reduction in sudden cardiac death was significant in all trials. The Yusuf at al meta-analysis also confirmed a reduction in total mortality, re-infarction and sudden death with long term [1-3 year] BB use, without specifying which subgroup benefitted most. Olsson’s review confirmed the reduction in mortality and sudden cardiac death up to 3 years post myocardial infarction, but the curves of death and sudden death diverged significantly only during the first year, and become parallel afterwards. Only the meta-analysis by Freemantle, which showed an annual reduction of 1.2 deaths and 0.9 re-infarctions per 100 patients treated with BBs, provides evidence that the beneficial effect on mortality with BB treatment after AMI may continue to accrue after the first year. Kernis at el showed that beta-blockade in patients treated with PCI lowered six-month mortality and MACE, but only significantly in patients with depressed ejection fraction and multi-vessel CAD []. BB treatment with PCI produced a decrease in 1-year mortality, but this was driven by the decrease in in-hospital deaths [].
It should be noted that the differences or similarities in findings across the trials does not appear to be related to differences in the beta-blocking agent used. The majority of the studies employed metoprolol or atenolol, beta-1 selective agents, and the type of long or short term benefit seen, if present at all, did segregate to one agent or the other. Trials which employed non-selective agents, including BHAT and the Norwegian Timolol Trial, demonstrated similar findings. The APSI trial, which studied acebutolol, a beta-1 selective agent with sympathomimetic activity, also demonstrated similar findings to studies with metoprolol or atenolol. The meta-analysis by Freemantle et al noted that trials employing agents with sympathomimetic activity showed a trend toward decreased benefit. Thus, variability of the findings does not appear to be explained by differences in the beta-blocker used. Studies of the use of agents such as carvedilol or bisoprolol in post-AMI patients show clear reductions in mortality, but these were demonstrated primarily in heart failure populations, with Left Ventricular systolic dysfunction. Therefore, these studies are not included in the present discussion.
This review of the literature demonstrates that the data upon which current guidelines for beta-blocker use post-AMI are based is conflicting, and is at best suggestive rather than directive. The majority of the data suggests that there is a reduction in total mortality, re-infarction and sudden cardiac death in the first 3 years of beta-blocker use, especially in patients who are at high risk, but the benefit emerges in the early phase after MI. Additional benefit does not appear to reliably accrue beyond one year. Overall, low-risk patients benefit the least from BB therapy, and thus it is reasonable to conclude that there is not strong support for continued treatment of patients with BB for more than one year post MI, particularly in low risk patients or those with preserved LVEF.
In conclusion, it can be recommended that acutely, all hemodynamically stable AMI patients receive BB to reduce chest pain, as well as to reduce the risk of re-infarction and Ventricular arrhythmias. There may be a slight reduction in mortality if the patient has not previously been treated with BB. However, it remains inconclusive whether BB use beyond one year truly reduces mortality in the current era of AMI and post-AMI care, particularly in patients with preserved Left Ventricular systolic function. In these and other low risk patients (young, no arrhythmias or residual ischemia), prolonged use with Beta-Blockers is unlikely to confer mortality benefit. These findings can inform a practitioner’s decision regarding the risks and benefits of discontinuation of BBs in low risk patients, in the not infrequent clinical circumstance where discontinuation needs to be considered. It is important to keep in mind that most of the trials reviewed above were conducted before the widespread use of revascularization either by thrombolysis or PCI. Further studies are warranted to examine the effect of the duration of treatment with beta-blockers in asymptomatic patients treated with current medical therapy and interventions.
ACKNOWLEDGEMENT
Supported by: Department of Medicine Fellow Research Elective Program.
ABBREVIATIONS
ACS | = Acute coronary syndrome |
AM I | = Acute myocardial infarction |
BHAT | = Beta blocker heart attack trial |
BB | = Beta blockers |
LVE F | = Left ventricular ejection fraction |
LVSF | = Left ventricular systolic function |
MIAMI | = Metoprolol in acute myocardial infarction |
NYHA | = New york heart association |
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