Iii Other Third Generation Beta
LABETOLOL
Blocks the alpha-1, beta-1 and beta-2 receptors and alpha-1 receptor blokade is responsible for the vasodilator effect. It has a partial agonist effect and is metabolised mainly by the liver.
BUCINDOLOL
Bucindolol is a non-selective and lipophilic beta blocker with a higher affinity then beta receptors. Vasodilator effects seem to be due to direct alpha-1 blockade.
BEST failed to show any benefit of bucindolol for total mortality in Class III-IV heart failure patients when added to the usual care . In the Class IV patients bucindolol even increased the composite end point of death and heart failure hospitalisations in six-months follow-up. The annual mortality for Class IV patients in the placebo group of the BEST study was 28 % which was higher than CIBIS , COPERNICUS and MERIT-HF studies. It has been suggested that the Class IV patients in BEST study were much sicker than the other studies and this contributed to the less beneficial effect of bucindolol in the BEST study.
CELIPROLOL
Celiprolol is a third generation beta blocker with a weak beta-2 agonist activity and weak alpha 2 blocker and direct smooth muscle relaxing properties. It reduces peripheral vascular resistance and has similar antihypertensive effects to metoprolol, propronalol, atenolol and pindolol. In a study on heart failure patients comparing metoprolol, placebo and celiprolol, both drugs were well tolerated but celiprolol did not show any additional benefit .
Initiation Of Beta Blocker Therapy
Appropriate candidates for beta blocker therapy should be evaluated thoroughly before treatment is initiated. The evaluation should include a comprehensive history and physical examination, with special emphasis on the assessment of functional capacity and the appropriateness of diuretic therapy. An electrocardiogram should be obtained to exclude the presence of high-degree heart block. An approach to the evaluation and treatment of patients with chronic heart failure is presented in Figure 1.14
Heart Rate At Baseline And Mortality For Patients In Sinus Rhythm Or Af
For patients in sinus rhythm, there were 2,141 deaths among 14,166 patients over a mean follow-up period of 1.5 ± 1.1 years. Baseline heart rate was associated with all-cause mortality, with an HR of 1.11 per 10 beats/min , adjusted for baseline variables and treatment allocation. From the Kaplan-Meier analysis , higher baseline heart rates were associated with higher mortality in patients assigned to either placebo or beta-blockers.
Figure 2.
Baseline Heart Rate and All-Cause Mortality
Kaplan-Meier survival curves for sinus rhythm and atrial fibrillation in patients randomized to placebo or beta-blockers. Higher baseline heart rate is associated with higher risk for mortality in sinus rhythm but not in atrial fibrillation, with similar results in patients randomized to placebo or beta-blockers. bpm = beats per minute.
For patients in AF at baseline, there were 609 deaths among 3,034 patients , but there was no association between baseline heart rate and mortality .
The displays the modeling of heart rate as a continuous variable and the HR for death, according to baseline heart rhythm. Contrary to results in sinus rhythm, there was no relationship between baseline heart rate and mortality for those in AF . Sensitivity analyses showed similar results to the main findings .
Central Illustration.
Modeling of Heart Rate at Baseline and the Hazard of Death
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Ethics Approval And Informed Consent
Approval for this study was obtained from the institutional review board of Jimma University, College of Health and Medical Sciences. We fully explained the purpose and protocol of the study to all participants included in the study and written informed consent was obtained from each participant. The personal information was entirely confidential and protected. All methods were performed in accordance with the approved institutional guidelines.
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Minor Risks Of Beta Blockers
Many people choose not to take beta-blockers due to concerns of depression and sexual dysfunction, which this class of medications has been linked to. However, studies have shown that the risk is very low. To summarize these trials:4
- Beta blockers do not increase the risk of depression.
- There is a small increase in the risk of sexual dysfunction. To put this risk into perspective, for every 200 people treated with a beta blocker, one person will experience sexual dysfunction.
If you are concerned about these side effects, it is a good idea to have a discussion with your doctor, as your underlying health factors can further predict these risks.
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Data Synthesis And Analysis
We report categorical outcomes as numbers and continuous outcomes as median . We derived the raw event rates from individual studies and constructed 2×2 tables with raw number of events and total population of the trial. In trials that did not report raw event rates, investigators reported the percentage or proportion of patients having the event under consideration, which we rounded off to whole numbers by using the sample size of the population we then calculated the risk difference by using the formula 1/, where OR=odds ratio. We calculated number needed to treat and corresponding absolute risk reduction from the 2×2 tables. We abstracted data in duplicate, and the inter-rater agreement was good . Considering different lengths of follow-up for individual trials, and to account for censored data, we obtained the rates of outcomes for all trials with follow-up longer than 12 months and calculated the log hazard ratios from the event rates reported and mean duration of follow-up. We did standard pair-wise meta-analysis comparing blockers with comparators, with 95% confidence intervals. We also used a random effect model to calculate prediction intervals for all cause mortality, using RevMan v5.1 and Stata version 11. We assessed and quantified heterogeneity with the help of the I2 statistic computed with the Cochran Q test.
Comparison With Other Studies
A previous retrospective study attempted to compare different blockers in clinical use by using data from an administrative database.53 The authors concluded that atenolol and acebutolol were superior to metoprolol in reducing mortality in patients, whereas carvedilol and bisoprolol were not superior to metoprolol in improving survival. The population studied in that analysis was quite different from the population of randomized trials assessed in our studythe mean age of the population of that study was 77 years, whereas the mean age of the population in our analysis was 61 years, and the percentage of male patients was 49% in the study, whereas male patients comprised 76% of the population in our analysis. Also, ejection fraction was not accounted for in the analysis of the retrospective study, whereas the mean ejection fraction of the population in our analysis was 26%. Hence, the difference from our study, which pooled data from randomized trials only, can likely be explained by differences in the population studied and differences in the analytic methods.
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Adverse Effects Of Beta
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If you have been diagnosed with Heart Failure , you may have been prescribed a beta-blocker. A beta-blocker is a class of medications commonly used to treat HF, high blood pressure, heart attacks, and arrhythmias. While these drugs are life-saving, they come equipped with adverse effects. Knowing and understanding how to manage these side effects will help you navigate your new treatment.
What Is The Clinical Evidence Of Benefit From
Lancet.Br Heart J.
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If you have been diagnosed with Heart Failure , you may have been prescribed a beta-blocker. A beta-blocker is a class of medications commonly used to treat HF, high blood pressure, heart attacks, and arrhythmias. While these drugs are life-saving, they come equipped with adverse effects. Knowing and understanding how to manage these side effects will help you navigate your new treatment.
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What Are The Side Effects
Dizziness or lightheadedness: This may be strongest when you get out of bed or get up from a chair. Get up more slowly. Call your doctor or nurse if these symptoms don’t go away or are severe.
Tiredness, cold hands and feet, headache, nightmares, trouble sleeping, heartburn, diarrhea or constipation, or gas. Call your doctor or nurse if these symptoms don’t go away or are severe.
Sudden weight gain.Weight gain is common as your doctor increases your medication dose. Call your doctor if you gain 3 or more pounds in 1 day, or if you continue to gain weight for more than 2 days.
Increased shortness of breath wheezing trouble breathing skin rash slow, fast, or irregular heartbeat swelling of feet and lower legs chest pain. Call your doctor or nurse right away.
Severe vomiting or diarrhea. If you have these, you may become dehydrated, which can lead to low blood pressure. Call your doctor or nurse.
Also call your doctor or nurse if you have any other symptoms that cause concern.
Target Heart Rate Versus Target Dose
Whether clinicians should strive to achieve a target heart rate or a target dose of beta-blocker remains unanswered, and the authors of this paper were unable to reach a consensus. In this analysis, beta-blockers reduced mortality, regardless of baseline heart rates, for patients with HFrEF in sinus rhythm. All trial protocols, which form the basis for current international guidelines, requested titration to a target dose of beta-blocker, provided they were tolerated and did not cause excessive bradycardia. Dose-dependent improvements in LVEF and survival were observed in the MOCHA trial , although that trial included only 345 patients. No large trial has randomized patients to higher versus lower doses, although post hoc analyses suggest greater benefit from higher doses . A trial-level meta-analysis of 7 dose-ranging studies of beta-blockers provided inconclusive evidence of a dose relationship with mortality further prospective trials are required to clarify this issue.
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Circulatory State And Diuresis
Optimal management of intravascular volume results in maximal resting cardiac output and minimal congestion, thereby minimizing sympathetic activation. Patients with evident extravascular fluid retention should be diuresed until the disappearance of excess fluid and the normalization of jugular venous pressure . The diuresis is usually associated with improvement in perfusion. Before beta blocker therapy is initiated, patients should be stable on a maintenance diuretic regimen.
Data Extraction And Quality Assessment
Two independent reviewers abstracted data and appraised studies, with divergences resolved by consensus . They extracted key characteristics of studies and patients, including the following outcomes, reported at the longest available follow-up according to intention to treat principles: all cause mortality, cardiovascular death, sudden death, drug discontinuation, and change in left ventricular ejection fraction from baseline to follow-up. In addition, they appraised study validity according to the risk of bias tool recommended by the Cochrane Collaboration.
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How To Take Beta
You can take them in the morning, at meals, and at bedtime. When you take them with food, you may have fewer side effects because your body absorbs the drug slower.
Follow the label directions on how often to take it. The number of doses you take each day, the time allowed between doses, and how long you need to take the medication will depend on your condition. Older people typically take lower doses. Ask your doctor what to do if you miss a dose.
While you’re taking a beta-blocker, you may need to check your pulse every day. If it’s slower than it should be, contact your doctor about taking your beta-blocker that day.
Never stop taking a beta-blocker without speaking to your doctor first, even if you feel that it’s not working. Sudden withdrawal can worsen angina and cause heart attacks.
Data Collection And Individual Patient Data Integrity
A standardized data request form to obtain IPD from each trial has been published, along with search results and individual study demographics. IPD were obtained for all 11 trials identified in the systematic review, and data were extracted from original source files provided by the pharmaceutical companies and lead investigators. All data were cross-checked across different trial databases and compared with published reports. Discrepancies, inconsistencies, and incomplete data were checked against original case report forms and trial documentation to ensure IPD integrity. All 11 trial databases were then harmonized according to the standardized data request form to match patient characteristics and outcomes across all trials. Due to the small amount of missing data for relevant covariates, imputation was not performed.
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Achieved Versus Change In Post
A landmark analysis was performed, starting at an interim visit after expected dose titration for each surviving participant with a recorded interim heart rate . Mean heart rate was similar at the interim and final visits for surviving patients in sinus rhythm or AF, suggesting stable beta-blockade had been reached .
For patients in sinus rhythm, the heart rate achieved at the interim visit was more strongly associated with mortality than the change in heart rate from baseline . The lowest mortality in sinus rhythm was observed in patients who attained lower heart rates after beta-blocker therapy . Conversely, in patients with AF, neither attained nor change in heart rate were associated with survival .
Figure 4.
Heart Rate Measured at the Interim Visit and All-Cause Mortality for Patients Assigned to Placebo or Beta-Blocker
Kaplan-Meier survival curves censored from time of the interim visit , showing clear relationship between achieved heart rate and mortality for both placebo and beta-blocker patients in sinus rhythm but not in atrial fibrillation. Includes a post hoc grouping of heart rate that separates patients < 60 beats/min in the beta-blocker arm.
Beta Blocker Side Effects
Before prescribing a beta-blocker, your doctor will ensure that the medication is safe and indicated. Some potential risks and unwanted side effects of beta-blockers are outlined below.
- Weight gain: Fat accumulation is more likely with the older agents, such as metoprolol and atenolol. Weight gain usually occurs in the first initial months of treatment, but stops and reaches a plateau thereafter. The average weight gain is 1.2 kg.1
- Low blood sugars: This drugs class can worsen or extend a period of hypoglycaemia, or low blood sugar levels. This is especially concerning for people with diabetes. Beta-blockers can also mask the symptoms of low blood sugar, which may be problematic if people rely on symptoms alone to determine whether their sugars are low.2
- Worsening asthma and COPD: Some beta-blockers are not recommended for people with severe asthma or COPD, as they may cause narrowing of the respiratory tract and worsen respiratory symptoms. However, it was found that medications commonly used for asthma and COPD such as inhaled steroids are protective against this side effect3.
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Selection Criteria And Data Abstraction
A systematic review of the literature with meta-analysis was needed to identify all clinical trials evaluating beta-blockers for heart failure and reporting all-cause mortality. Eligible studies had to be placebo-controlled trials and provide information on the incidence of sudden cardiac death. Additional inclusion criteria included: treatment for > 30 days and follow-up 3 months. Studies of patients < 18 years, randomization to beta-blocker vs. an angiotensin converting enzyme , and/or beta-blockers in both arms were excluded from the analysis.
Abstracted data included eligibility criteria, baseline characteristics, study design , follow-up, and outcomes. Pre-specified outcomes of interest included SCD, cardiovascular death , and all-cause mortality. Outcomes were analyzed according to intention-to-treat. Study quality was formally evaluated using the Jadad score for the quality assessment of randomized controlled trials. For the purpose of this analysis, studies which had a score of 3/5 or more were considered high quality. The study selection process is shown in Figure .
Figure 1
PRISMA flow diagram for the meta-analysis. Study selection process according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
What If I Forget To Take It
If you forget to take a dose of your beta blocker, take it as soon as you remember, unless it is nearly time for your next dose. In this case, just leave out the missed dose and take your next dose as normal.
Never take 2 doses at the same time. Never take an extra dose to make up for a forgotten one.
If you often forget doses, it may help to set an alarm to remind you. You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.
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Who Can Take Beta Blockers
Beta blockers are not suitable for everyone. To make sure they are safe for you, tell your doctor before starting a beta blocker if you have:
- had an allergic reaction to a beta blocker or any other medicine in the past
- low blood pressure or a slow heart rate
- serious blood circulation problems in your limbs
- metabolic acidosis when there’s too much acid in your blood
- lung disease or asthma
Tell your doctor if you’re trying to get pregnant, are already pregnant or breastfeeding.
It’s important not to stop taking beta blockers without seeking your doctor’s advice. In some cases suddenly stopping the medicine may make your health condition worse.
Systolic Dysfunction In Heart Failure: Neurohormonal Theory
Left ventricular systolic dysfunction is a mechanical defect that results in the heart’s inability to pump oxygenated blood to peripheral tissues. The impact of this dysfunction is manifested in hemodynamic and physiologic abnormalities, including decreased cardiac output, elevated pulmonary capillary wedge pressure and decreased exercise tolerance. Historically, interventions to treat patients with heart failure have been directed at improving these hemodynamic end points. However, clinical trials found a lack of correlation between hemodynamic improvement and clinical improvement, and new strategies were sought.
Recent studies have revealed a correlation between prognosis in heart failure and plasma levels of such neurohormones as endothelin,14 norepinephrine15 and renin,16 among others. Neurohormones have also been shown to stimulate necrosis, fibrosis and apoptosis in the heart. As a result, a neurohormonal hypothesis has evolved to describe how activation of these neurohormonal systems may cause progression of heart failure.16,17
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