Definition Of Heart Failure
Congestive heart failure is a broad term used to describe a clinical condition resulting from the inability of the heart to adequately pump blood and causing symptoms such as orthopnea, dyspnea on exertion and edema. In practice, congestive heart failure is used to describe these symptoms whether they result from diastolic dysfunction, which is a condition of impaired ventricular filling, or systolic dysfunction, which is a condition of impaired ventricular emptying.
As the understanding of heart failure has advanced, it has become important to separate systolic dysfunction from diastolic dysfunction because the etiology, treatment and prognosis of these disorders is quite different. The discussion in this article is limited to heart failure resulting from left ventricular systolic dysfunction, defined as an ejection fraction of less than 40 percent.
Carvedilol And Diabetes Mellitus
In COMET, diabetic events occurred in 22% less carvedilol patients than in metoprolol patients . New onset diabetes was diagnosed in 10.4% versus 12.6% cases in the carvedilol and metoprolol treatment groups, respectively . Patients with diabetes at baseline had an increased mortality, compared to non-diabetics . Both diabetics and non-diabetics at baseline had a similar reduction in mortality with carvedilol compared to metoprolol . Thus, whereas there was a high prevalence and incidence of diabetes in COMET patients, new onset diabetes was more likely to occur during treatment with metoprolol than during treatment with carvedilol.
In the Gemini study, in patients with diabetes and hypertension, in patients not taking insulin sensitizers, metoprolol tartrate significantly worsened insulin resistance, an effect not seen with carvedilol . Similarly, in patients after an MI, carvedilol improved insulin resistance . In the latter study, carvedilol also reduced total cholesterol and LDL levels to a greater extent than metoprolol. Reductions in triglycerides, total cholesterol and non-HDL levels were also reported to be significantly greater with carvedilol than with metoprolol in the GEMINI study , whereas a different report of the latter study indicated more weight gain with metoprolol than carvedilol .
Taken together, carvedilol may also be a better choice than metoprolol in heart failure in combination with determinants of the metabolic syndrome.
When Beta Blockers Are Prescribed
Beta blockers do not strengthen the heart, they simply stop the nervous system from overstimulating it. This prevents the heart muscle from overworking itself to hypertrophy due to excessive strain, which can lead to cardiomyopathy, Dr. Reed explains.
While beta blockers can reduce damage to the heart by taking the strain off, Dr. Shill explains that if taken incorrectly they could actually weaken the heart. When not taken as prescribed, they can do more harm than good. Beta blockers can cause a dangerously low heart rate called bradycardia which can lead to low blood pressure. This can cause symptoms like dizziness, nausea, fainting, lack of concentration, or blurred vision.
So long as a patient is stable and the right beta blocker is prescribed in the right dose, beta blockers can be successfully used to treat heart failure. The sympathetic nervous system is overacting and putting strain on the heart and that is why beta blockers will be initiated and then continued, Dr. Reed says. After a bout of acute heart failure, most patients will continue beta blocker therapy. Beta blockers have been shown to reduce mortality, and there is strong evidence supporting their use.
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Why Beta Blockers Work
Left ventricular systolic dysfunction is associated with activation of a host of interconnected neurohormonal adaptive mechanisms, most notably the sympathetic and renin-angiotensin-aldosterone systems. Chronic activation of these mechanisms exerts deleterious hemodynamic and direct cardiotoxic effects and contributes to the progressive deterioration of ventricular function. Attenuation of these mechanisms is associated with improvement in survival. This has been demonstrated for angiotensin-converting enzyme inhibitors,912 beta blockers18 and spironolactone,13 and is suggested for other classes of drugs under evaluation.
Data Sources And Search
We searched for randomized trials in CINAHL , the Cochrane Collaboration Central Register of Controlled Trials , Embase , Medline/PubMed , and Web of Science . We restricted our searches to human studies, clinical trials, and controlled or randomized trials. We used the keywords and medical subject headings adrenergic beta-antagonists, heart failure, and congestive, as well as additional text words in combination with an established search strategy for Medline/PubMed.1112 We also hand searched bibliographies of identified studies, recent meta-analyses of blockers in heart failure, heart failure guidelines, and 2008-11 conference proceedings of the American College of Cardiology, American Heart Association, and European Society of Cardiology scientific sessions. We restricted our search to publications in the English language.
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Outcomes And Effect Measures
The primary outcomes for this analysis were all-cause mortality and cardiovascular death, which included additional deaths reported after the censor date for seven studies.,, Secondary outcomes were the first cardiovascular hospitalization and the composite of cardiovascular death and cardiovascular hospitalization . All secondary outcomes were based on events from the study period only and do not include the MDC trial which did not collect this information. Three patients had missing event dates and were excluded from outcome analyses.
Most of the trials had limits for LVEF as inclusion or exclusion criteria, however these were typically defined preceding randomization . In this analysis, we used the baseline value of LVEF recorded in individual patient case report forms or core laboratory assessment, which in some patients was above the entry criterion according to that particular study. LVEF was analysed as a continuous variable to model interactions with outcomes, and classified as < 20%, 2025%, 2634%, 3539%, 4049%, and50%, as well as < 40%, 4049%, 50% to align with guideline phenotypes.
Side Effects Of Beta Blockers
Most people taking beta blockers have either no or very mild side effects that become less troublesome with time.
Contact your GP if you’re having symptoms that bother you or last more than a few days.
Side effects commonly reported by people taking beta blockers include:
- feeling tired, dizzy or lightheaded
- cold fingers or toes
- difficulties sleeping or nightmares
It happens rarely, but some people have serious side effects when taking beta blockers.
Tell a doctor straight away if you have:
- shortness of breath with a cough that gets worse when you exercise , swollen ankles or legs, chest pain, or an irregular heartbeat these are signs of heart problems
- shortness of breath, wheezing and tightening of your chest these can be signs of lung problems
- yellow skin or the whites of your eyes turn yellow these can be signs of liver problems
These are not all the side effects of beta blockers. For a full list, see the leaflet inside your medicine packet.
You can report suspected side effects using the Yellow Card Scheme.
For more information on the side effects of beta blockers, read about the specific medicine you take in our Medicines A to Z.
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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
The No 1 Reason People Stop Taking Beta
The top reason patients stop using beta-blockers is admission to the hospital for various conditions, not just heart failure, Dr. Tang says. However, most people should not stop, even if they are hospitalized, unless the doctors decided that it is more harm than good.
Research shows that patients fare better when they continue taking beta-blockers while in the hospital, even with acute heart failure.
An inability to tolerate beta-blockers indicates a worsening heart condition, says Dr. Tang. Other testing may be necessary to determine if the heart is too weak for beta-blockers.
This may even apply for patients whose heart function has recovered to the normal range. Recent clinical studies have shown that, even in those with full recovery of their heart structure and function, stopping drugs like beta-blockers can reverse the recovery course and can be detrimental, he adds.
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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.
How Does Metoprolol Help With Heart Failure
Metoprolol, a relatively selective beta1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity. The drug has an established role in the management of essential hypertension and angina pectoris, and more recently, in patients with chronic heart failure.
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Should I Avoid Certain Drugs While Taking Beta
A beta-blocker is often prescribed with other medications such as a diuretic, ACE inhibitor, angiotensin receptor neprilysin inhibitor , or angiotensin receptor blocker . If you have side effects after taking your medications together, call your doctor or nurse. You may need to change the times you take each drug.
Itâs important that your doctor be aware of all the medications you are taking, as some may interact with beta-blockers. Talk to your doctor before taking any new drug, including over-the-counter drugs, herbs, and supplements.
Show Sources
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.
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Cautions With Other Medicines
There are some medicines that may interfere with the way that beta blockers, including beta blocker eyedrops, work.
Tell your doctor if you’re taking:
- other medicines for high blood pressure. The combination with beta blockers can sometimes lower your blood pressure too much. This may make you feel dizzy or faint
- other medicines for an irregular heartbeat such as amiodarone or flecainide
- other medicines that can lower your blood pressure. These include some antidepressants, nitrates , baclofen , medicines for an enlarged prostate gland like tamsulosin, or Parkinson’s disease medicines such as levodopa
- medicines for asthma or chronic obstructive pulmonary disease
- medicines for diabetes, particularly insulin beta blockers may make it more difficult to recognise the warning signs of low blood sugar
- medicines to treat nose or sinus congestion, or other cold remedies
- medicines for allergies, such as ephedrine, noradrenaline or adrenaline
- non-steroidal anti-inflammatory medicines , such as ibuprofen. These medicines may increase your blood pressure, so it’s best to keep them to a minimum
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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History Structure And Classification Of Adrenergic Beta Receptors
To date, three subtypes of -receptors have been identified the existence of a fourth subtype, called 4, has been proposed to explain the sympathomimetic effects of some atypical -agonists known to be inactive on the classical-receptors however recent evidence suggest that the putative 4 receptor is more likely a novel functional state of 1 receptor .
Although the main intracellular pathway activated by -ARs is Gs signaling, it has been demonstrated that stimulation of -ARs can also activate Gi proteins, MAP kinases and other proteins involved in the control of cell cycle and apoptosis , in a subtype-specific manner, thus differentially influencing cardiomyocytes fate. These evidence suggest that modulation of -ARs can impact cardiac pathophysiology in different and multiple ways, well beyond than simply controlling heart mechanics.
Association Of Lvef With Mortality
Left ventricular ejection fraction at baseline was inversely associated with all-cause mortality, with an adjusted HR of 1.16 for each 5% lower LVEF . Figure displays the hazard of all-cause mortality with LVEF 35% as the reference. The association between LVEF and prognosis was stronger for patients in sinus rhythm than AF . Patients with LVEF50% had the lowest mortality despite their older age all-cause and cardiovascular mortality were 10.4% and 6.3% respectively for those with LVEF50%, compared to 26.7% and 21.7% for those with LVEF < 20%. Mortality was predominantly cardiovascular regardless of aetiology, both for patients in sinus rhythm and AF , and mostly attributed to sudden death or worsening heart failure.
Hazard of all-cause mortality across the spectrum of LVEF. Hazard ratio and 95% confidence intervals for all-cause mortality according to baseline left ventricular ejection fraction , relative to a patient with an LVEF of 35%. Hazard ratios are fitted using a Cox proportional hazards regression model, adjusted for treatment, age, gender, previous myocardial infarction, systolic blood pressure, heart rate, use of angiotensin inhibitors/receptor blockers and diuretics, and stratified by study.
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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 .
Chief Areas Of Impact
- American College of Cardiology
- European Society of Cardiology
Beta-blockers are now a worldwide mainstay of heart failure treatment recommended in all international guidelines for chronic heart failure: this is a reversal of previous practice since they were completely contraindicated in this condition up to the late 1990s. Imperial College researchers were pivotal in defining beta-adrenoceptor/beta-blocker mechanisms in failing human hearts and translating the benefits into clinical practice. Imperial College researchers designed and led the COMET and SENIORS beta-blocker trials for heart failure and the UK arm of the COPERNICUS trial. These studies helped establish beta blockers in modern heart failure management: these are now the 4th most commonly prescribed drugs worldwide.
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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.