Why Beta Blockers Used In Heart Failure?

Why Beta Blockers Used In Heart Failure

Beta blockers block the release of the stress hormones adrenaline and noradrenaline. They are widely prescribed for angina, heart failure and some heart rhythm disorders, and to control blood pressure. They are usually tolerated well without significant side effects.

Should beta blockers be given in heart failure?

Drugs called beta-blockers perform four main tasks essential for people with heart failure:

Improve your heart ‘s ability to relaxDecrease the production of harmful substances your body makes in response to heart failure Slow your heart rate Improve the heart’s pumping ability over time

If you have heart failure, you need beta-blockers – even if you do not have symptoms. Beta-blockers are prescribed for patients with systolic heart failure and improve survival, even in people with severe symptoms. There are several types of beta-blockers, but only three are approved by the FDA to treat heart failure:

Bisoprolol ( Zebeta ) Carvedilol ( Coreg ) Metoprolol ( Toprol )

How do beta blockers improve cardiac function in HF?

The binding of β-adrenergic agonists such as norepinephrine and isoproterenol to the β-1 adrenergic receptor (AR) in the sarcolemma of the ventricular myocyte increases intracellular levels of cAMP via G s protein-induced stimulation of adenyl cyclase.

CAMP activates protein kinase A (PKA), which causes phosphorylation of proteins involved in Ca 2+ homeostasis, such as phospholamban and the L-type Ca 2+ channel, increasing the intracellular calcium ion concentration ( i ) transient, and thus causing a positive inotropic effect. It is now very well established that patients with congestive heart failure due to ischemic or idiopathic dilated cardiomyopathy are in a hyperadrenergic state.1 Treatment of these patients with β-adrenergic receptor-blocking drugs reduces morbidity and mortality, 2 improves ventricular function, and reverses pathological remodeling.3 Clinical and experimental animal studies have suggested a number of mechanisms by which chronic exposure to this class of drugs, which have a negative inotropic effect in normal myocardium, could have an apparently paradoxical beneficial effect in failing myocardium.

Seminal work by Bristow and associates 4 showed that β-1 AR density is reduced in the failing myocardium, and receptor density is increased by treatment with some β-AR blockers.5 An increase in β-receptor density may restore toward normal an available positive inotropic reserve in patients with heart failure.

  • In isolated myocytes, a cytotoxic effect of prolonged adrenergic stimulation can be demonstrated, 6 suggesting that β-blockade may reduce a deleterious effect of the chronic hyperadrenergic state on myocyte survival.
  • Treatment with β-blockers also slows the heart rate.
  • Because failing myocardium displays a decrease in contractility with increasing rate of stimulation, 7 this may improve ventricular function.

At slow rates of stimulation, the myocyte action potential is prolonged, allowing for more Ca 2+ influx via Na/Ca exchange, and permitting more complete relaxation and reloading of the sarcoplasmic reticulum (SR) with Ca 2+, despite a reduced expression of SR Ca 2+ ATPase SERCA2a, which is present in the myocardium of many patients with heart failure.8 Finally, the reduced expression of SERCA2a and α-myosin heavy chains 9 may be restored toward normal by changes in gene expression induced by β-blocking drugs.10 This could improve systolic and diastolic function.

  • In this issue of Circulation, Reiken et al 11 describe another possible mechanism by which β-blockers may improve SR function and thus calcium homeostasis and contractility in failing myocardium: A reduction in PKA-mediated hyperphosphorylation of the SR calcium release channel.
  • The cardiac calcium release channel, or ryanodine receptor 2 (RyR2), is a macromolecular complex comprised of homotetramers, with each of the 4 subunits containing a PKA phosphorylation site and capable of binding 1 molecule of FK506-binding protein (FKBP12.6).

The channel complex, which is opened by exposure to Ca 2+ entering the myocyte via the L-type Ca 2+ channel during excitation-contraction coupling, also includes phosphatases, which can induce dephosphorylation. As Reiken et al 11 discuss, work from their group has shown that FKBP12.6 is dissociated from RyR2 by exposure to FK506, or by hyperphosphorylation, and this causes the RyR2 calcium release channel to display an increased sensitivity to Ca 2+, a greater open probability resulting in a “leaky” channel that could cause SR Ca 2+ depletion, and impaired cooperativity between RyR subunits.

  1. Reiken et al 11 studied myocardium obtained from hearts of 9 patients with heart failure not treated with β-blockers, from 10 patients with heart failure treated with β-blockers, and from 5 normal patients.
  2. In patients with heart failure, there was a reduced binding of FKBP12.6 to RyR2 associated with hyperphosphorylation of RyR2 detected by a back phosphorylation technique and abnormal RyR2 channel function in planar lipid bilayers characterized by an increased opening probability and greater prevalence of subconductance states.

All these abnormalities were reversed toward normal in myocardium from patients with heart failure who had been treated with β-blockers. Reiken et al 11 suggest that RyR2 hyperphosphorylation due to increased activation of PKA (and reduced phosphatase activity) results in dissociation of FKBP12.6 from RyR2, thus inducing a SR Ca 2+ leak with SR Ca 2+ depletion and hence a negative inotropic effect.

Treatment with β-blockers is proposed to improved myocardial function by decreasing the degree of phosphorylation of RyR2, thus decreasing the degree of dissociation of FKBP12.6 and enhancing SR function. It is somewhat surprising that hyperphosphorylation of RyR2 is present in heart failure, in which there is downregulation of β-ARs.

Indeed, some studies have shown that phosphorylation of phospholamban, another substrate for PKA-mediated phosphorylation, is actually reduced in myocardium from patients with heart failure.12 However, recent work 13 has demonstrated that there are discrete microdomains within cardiac myocytes in which effects of PKA may be regulated by the binding of the enzyme to its anchoring proteins and by co-localization of phosphodiesterases and phosphatases that can regulate regional concentrations of cAMP and of phosphorylated substrates, respectively.

  1. Variable alterations in these factors may explain why one target of PKA might be hyperphosphorylated whereas another might be hypophosphorylated in the failing myocyte.
  2. There are data from several experimental studies in animal models that are consistent with the hypothesis that hyperphosphorylation of RyR2 does occur with heart failure.11 That this causes dissociation of FKBP12.6 from RyR2 and results in SR Ca 2+ depletion is supported by work of Yano et al.14 These investigators found that defective interaction of FKBP12.6 with RyR2 in a canine model of pacing-induced heart failure is associated with an abnormal SR Ca 2+ leak, which they suggest may contribute to impaired function of the myocardium.

In addition, we recently reported that dissociation of FKBP12.6 from RyR2 by exposure of rabbit ventricular myocytes to FK506 causes depletion of SR Ca 2+ stores and a resulting decrease in the myocyte i transient.15 Despite these supportive findings, there are some results that seem to challenge the concept that hyperphosphorylation-induced dissociation of FKBP12.6 is an important factor in abnormal Ca 2+ homeostasis in heart failure.

  1. Jiang et al 16 have reported that RyR2 isolated from failing human myocardium displayed no differences in vitro in open probability or the incidence of subconductance states as compared with controls.
  2. In addition, they detected no difference in the degree of RyR2 phosphorylation.
  3. Preliminary work by Terentyev et al 17 has shown that in permeabilized myocytes from rats with heart failure induced by chronic isoproterenol administration, exposure to phosphatases PP1 and PP2a induced activation of Ca sparks and depletion of Ca 2+ stores.

They suggest that their results are inconsistent with the idea that heart failure is associated with hyperphosphorylation of RyR, rendering the Ca 2+ release channel leaky to Ca 2+, To some extent, these discrepancies may result from the fact that different experimental techniques have been used in different animal models of heart failure, and that different species were used.

For example, dissociation of FKBP12.6 from RyR2 by exposure to FK506 is associated with an increase in the i transient in rat 18 and mouse 15 myocytes, but causes a decrease in the i transient in rabbit myocytes.15 Nevertheless, the importance of hyperphosphorylation of RyR2 in influencing myocyte contractility in heart failure needs and is certain to receive further investigation.

Finally, we should consider whether phosphorylation-induced dissociation the FKBP12.6 from RyR2 is important in normal physiology and whether alteration of the FKBP12.6–RyR2 interaction may be significant in other clinical situations. Reiken et al 11 suggest that the acute increase in RyR2 phosphorylation induced by PKA may be a component of the “fight or flight” response by increasing RyR2 sensitivity to Ca 2+ and thus enhancing SR Ca 2+ release and the i transient.

This would cause an acute increase in contractility, along with PKA-induced increases in the SR Ca 2+ uptake induced by phospholamban phosphorylation, and the increase in the L-type Ca 2+ current induced by phosphorylation of the Ca 2+ channel. This is plausible, but one might question why a positive inotropic effect, rather than a negative inotropic effect resulting from depletion of SR Ca 2+ due to Ca 2+ release channel leakiness, would predominate in the presence of hyperphosphorylation-induced dissociation of FKBP12.6 from RyR2.

The reason may relate to the degree to which SR Ca 2+ stores can be maintained in the face of an increased SR Ca 2+ leak. For example, FK506 induces depletion of SR Ca 2+ in rabbit myocytes and decreases the i transient, whereas in mouse SR Ca 2+ stores are not depleted and FK506 increases the transient.15 Thus, in normal myocardium, during sympathetic stimulation with activation of β-adrenergic receptors, stimulation of SR Ca 2+ uptake by phosphorylation of phospholamban might be sufficient to maintain SR Ca 2+ stores despite a SR Ca 2+ release channel leak with a resulting positive inotropic effect due to increased sensitivity of RyR2 to Ca 2+,

In failing myocardium, because of downregulation of SERCA2a and possibly reduced phosphorylation of phospholamban, 12 this compensatory increase in SR Ca 2+ uptake might be inadequate to maintain SR Ca 2+ stores. The immunosuppressive actions of FK506 (tacrolimus) are well known and result from the ability of a complex of FK506 and FKBP to bind to calcineurin and inhibit its phosphatase activity, resulting in the inhibition of T-lymphocyte activation.19 Use of FK506 in pediatric transplant recipients has been reported to be associated with the development of hypertrophic cardiomyopathy.20 Long-term exposure to ryanodine, which impairs SR Ca 2+ release channel function, has been reported to induce hypertrophy in rats.21 Therefore, FK506 could possibly induce hypertrophy in young patients because of its ability to cause dissociation of FKBP12.6 from RyR2, thus inducing SR dysfunction.

No significant myocardial effects of the use of tacrolimus in adult patients have been recognized, but could theoretically occur. Further study of the clinical significance of modulation of RyR2 function by drugs, intracellular signaling pathways, and other RyR2-associated proteins such as sorcin 22 in heart failure and other conditions is clearly warranted.

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Which beta blocker is best for heart failure?

BETA-BLOCKER SELECTION AND DOSAGE – Currently, no data indicate the superiority of one beta blocker over another in the treatment of heart failure. Comparative trials are pending. Carvedilol is the only agent labeled by the FDA for use in patients with heart failure.

It is also the only agent that is available in the appropriate starting dosage (3.125 mg twice daily). The starting dosages for metoprolol tartrate, metoprolol succinate and bisoprolol require that the tablet in the smallest available dose size be split into fourths, which may be a cumbersome task for some patients.

In addition, dividing the metoprolol succinate tablet into fourths may disrupt the delivery system, although it is not known if tablet division would have an adverse clinical impact. Metoprolol tartrate and bisoprolol are the least expensive of these agents ( Table 6 ),

Once the patient has tolerated the starting dosage of the selected beta blocker, the dosage should be doubled every two to four weeks as tolerated. While the dosage is being titrated, the patient should be monitored for signs of worsening heart failure, hypotension or bradycardia. If symptoms develop, the dosage may need to be held at the current level or decreased; in some patients, the drug may need to be stopped.

Otherwise, the dosage should be increased until the target dosage is achieved or the patient is receiving the maximal tolerated dosage, if below the target level. Once the desired dosage has been reached, no further adjustments need to be made. Even if the patient’s symptoms stabilize or the ejection fraction normalizes, most experts recommend continuing beta-blocker therapy indefinitely.

How do beta-blockers act in CHF?

Abstract – Sympathetic activation leading to raised levels of catecholamines is one of the earliest responses to the fall in cardiac output that occurs in chronic heart failure (CHF). Raised catecholamine levels have numerous adverse effects that can be counteracted by beta-blockers.

  1. For example, the increased heart rate associated with sympathetic activation is associated with a poor prognosis in CHF.
  2. In the major beta-blocker trials in CHF, a reduction in mortality of about 35% was consistently demonstrated with beta-blockade, which was associated with a reduction in heart rate of 10–15 bpm.

The resting heart rate predicts longevity in many mammalian species. A limited ability to increase heart rate during exercise (chronotropic incompetence) in left ventricular (LV) dysfunction and CHF also predicts mortality. Beta-blockers increase heart rate variability by rebalancing the sympatho-vagal axis.

How do beta-blockers improve mortality in heart failure?

The Impact of Treatment with Beta-Blockers upon Mortality in Chronic Heart Failure Patients 1 University Clinic of Cardiology, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia Find articles by 2 University Clinic of Toxicology and Urgency Medicine, Ss Cyril and Methodius University of Skopje, Skopje, Republic of Macedonia Find articles by Received 2015 Dec 16; Revised 2016 Jan 7; Accepted 2016 Jan 23.

  • © 2016 Borjanka Taneva, Daniela Caparoska.
  • This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
  • Besides the conventional therapy for heart failure, the diuretics, cardiac glycosides and ACE-inhibitors, current pharmacotherapy includes beta-blockers, mainly because of their pathophysiological mechanisms upon heart remodeling.

The study objective was to assess the cardiovascular mortality in the beta-blocker therapy group and to correlate it with the mortality in the control group as well as to correlate the combined outcome of death and/or hospitalization for cardiovascular reason between the two groups.

The study included 113 chronic heart failure patients followed up for a period of 18 months. The therapy group received conventional therapy plus the target dose of beta blockers, and the control group received the conventional therapy only. The therapy group was divided in three separate subgroups in terms of the type of beta-blocker (Metoprolol subgroup, Bisoprolol and Carvedilol subgroup).

To compare the mortality and the combined outcome, the RRR (relative risk reduction) and NNT (number needed to treat) were used, as well as the survival analysis by Kaplan-Meier. The results showed the following: in regards of the cardiovascular mortality, the relative risk for death in the therapy group was 34%, which, though statistically not significant, is of great clinical significance.

  • In regards of the combined outcome (death and/or number of hospitalizations) the results showed a RRR of 40% in the therapy group compared to the control group, which is statistically highly significant.
  • The study confirmed that patients with stable chronic heart failure, treated with optimal doses of beta-blockers, show a significant reduction of the risk from death as well as combined outcome (death and/or number of hospitalizations).

Keywords: heart failure, beta-blockers, mortality, combined outcome, relative risk reduction Heart failure is a pathophysiological condition when the abnormal heart function results in a failure of the heart to achieve blood output adequate to meet the requirements of the tissue metabolism.

In condition of heart failure as a response to the heart dysfunction, several neuro-endocrine systems are activated, as well as the sympathetic nervous system. Norepinephrine and plasma-catecholamine levels are increased and correlate with mortality rate, but the density of myocyte beta-1 receptors is lowered in heart failure patients.

Beta-blockers inhibit the activity of norepinephrine and enhance the density of beta-1 receptors. By lowering the heart rate they lower the oxygen demand, prolong the diastole, resulting in a better myocardial perfusion and less malignant arrhythmias.

They protect the heart of the direct cardiotoxicity of the catecholamines, They also suppress several activated neurohumoral systems in heart failure: rennin-angiotensine system and endothelyne-1 system, a powerful vasoconstrictor, Metoprolol and Bisoprolol are beta-1 selective, and Carvedilol is a potent antagonist of beta-1, beta-2 and also alfa-1 receptors.

It defers from the other beta-blockers with the effect upon the polymorphonuclear cells and its antioxidant activity, Beta–blockers are recommended for treatment of all patients with stabile heart failure from ischemic or non-ischemic etiology and reduced left ventricular ejection fraction in NYHA Class II to IV, as a standard therapy, including ACE-inhibitors and diuretics.

Despite their long term benefit they can make an initial worsening of the symptoms, and therefore, we should start their application carefully, starting with a low dose and gradually raising it to the target level, The aims of the study were: to assess mortality rate in the group treated with the target dose of beta-blockers (the therapy group), compared with the group on conventional therapy (the control group).

To compare the combined outcome (mortality and/or number of hospitalizations from cardiovascular reasons) between the two groups; to compare mortality as well as the combined outcome, regarding different types of beta-blockers in the therapy group (Metoprolol, Bisoprolol and Carvedilol); and to compare the mortality of each of the subgroups from the therapy group with the mortality in the control group.

One hundred and thirty five patients with verified heart failure were investigated in the Outpatient department of the Cardiology Clinic in a period of two years. Out of 135, 113 patients underwent a complete investigation, and 22 of them were excluded from the study due to a worsening of the condition in the titration period.

The follow up period of these 113 patients was 18 months. The minimum follow up period was 3 months. The patients were divided in 2 groups, statistically not different in age and gender. The first group was treated by conventional therapy and target dose of beta-blocker (the therapy group), and the second by conventional therapy only (the control group).

  • The therapy group was divided in 3 subgroups according to the type of beta-blocker: a subgroup with Metoprolol, Bisoprolol and Carvedilol.
  • Inclusion criteria: Age 40-70 years; Verified stable chronic heart failure: clinically according to the classification of the NYHA Functional Class from II –IV, and by echocardiography with a confirmed ejection fraction (EF%) of 45% or less.
  • The patient was required to be stable more than one month before included in the study.
  • The investigation included: complete laboratory analyses every 3 months, electrocardiogram once a month, one and two-dimensional transthoracic echocardiography every 3 months.

We compared mortality and the combined outcome between the two groups. To simplify the combined outcome we quantified this parameter by scoring other parameters taking part in it: (1) Number of hospitalizations (each hospitalization is scored by 1); and (2) number of acute attacks of chronic heart failure (each attack is scored by 1). The study was clinical, prospective, interventional and controlled. We investigated 38 variables and compared the data of the 2 groups at the beginning of the follow up (the zero time) and at the end of follow up, using Student t-test for numerical and Chi square test for nominal parameters. To compare the variables of interest between the three subgroups in the therapy group, we used ANOVA-one way test. We calculated the relative risk reduction and the number needed to treat to prevent the outcome in one patient (RRR and NNT) for the variables of the primary objective (mortality and the combined outcome-mortality and number of hospitalizations from cardiovascular causes). We made an analysis of the complete survival of all the groups and compared the survival between the control and therapy group and all the therapy subgroups separately with the Kaplan-Meier method. A p value of < 0.05 was taken to be statistically significant. Out of a total of 113 patients with chronic heart failure with NYHA-FC II–IV in a stable clinical condition, 60 were with a non-ischemic and 53 with ischemic heart failure. Ninety one of them were men and only 21 women (81.5% and 19.55% respectively), with a mean age of 57.3 ± 8.6 years. During the follow up the total mortality was 15 (13.2%). The total patient population is divided in 2 groups, control and therapy group. The therapy group is divided in 3 subgroups, Metoprolol, Bisoprolol and Carvedilol.

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  1. When comparing the parameters in the total population group between the survived and the patients who died, at zero time and at the end of the follow up, there was a statistically lower ejection fraction at the end of the follow up in the group of the patients who died, as well as lower ΔEF%, higher number of hospitalizations, more frequent attacks of acute heart failure, higher NYHA-FC at the beginning and at the end of the follow up and also higher NYHA-score at the end of follow up, but regarding systolic and diastolic blood pressure, the values were statistically lower in the group of patients who died.
  2. CER = the number of patients who died divided by the number of the patients in the control group.
  3. EER = the number of patients who died divided by the number of the patients in the therapy group.
  4. 95%CI (confidence interval) is the interval (the borders) between the events.
  5. CER= n (events)/total n EER= n (events)/total n
  6. RR= EER/CER RRR %= (CER-EER)/CER x 100
  7. NNT= 1/(CER-EER)
  8. Regarding mortality rate of the patients with the target dose of beta-blockers, compared to the control group, there wasn’t any statistically significant difference (Chi square test), but the RRR%, although the value of 34% was also statistically not significant, it had a substantial clinical value.

Regarding the combined outcome (mortality and/or hospitalization), the therapy group showed a statistically significant improvement (p < 0.0008). RRR% was 40% and NNT was 3.03, which indicates that if we treat 3 patients with a target dose of beta-blockers, we might prevent the combined outcome in one patient. The mortality in the 3 therapy subgroups did not show a statistically significant difference when compared to the control group, but the combined outcome (mortality and/or hospitalizations) in the 3 subgroups, separately, when compared to the control group, showed a statistically significant improvement. Regarding RRR% and NNT, there was a major improvement for both outcomes in all the 3 subgroups of beta blockers, but the Carvedilol subgroup showed highest values for RRR% (mortality - 56%, and the combined outcome - 38%) (,, ). Clinical and laboratory parameters for the total patient population (control and therapy group)

Variable n/M ± SD
Gender: men     women 91 (80.5%) 22 (19.5%)
Age 57.35 ± 8.6
Weight (in zero time) – kg 76.18 ± 11.6
Weight (end of follow up) kg 70.81 ± 12.3
BMI (in zero time) kg/m 2 26.11 ± 2.8
BMI (end of follow up) 24.4 ± 12.5
Htc (in zero time) vol% 0.39 ± 0.05
Htc (end of follow up) 0.37 ± 0.05
Scr (μmol/l) 84.53 ± 8.4
Alb (g/l) 44.01 ± 3.1
Total. lipids (g/l) 8.87 ± 1.3
HDL (mmol/l) 1.13 ± 0.2
LDL (mmol/l) 3.51 ± 0.7
Triglicerids (mmol/l) 1.53 ± 0.5
Na (mmol/l) 141.7 ± 2.6
K (mmol/l) 4.65 ± 0.4
ECG-zero time 1.66 ± 1.15
ECG-end of follow up 1.82 ± 1.17
EF % (zero time) 36.79 ± 6.6
EF % (end of follow up) 37.3 ± 8.3
ΔEF% 1.17 ± 6.8
NYHA-FC(zero time) 3.27 ± 0.7
NYHA-FC(end of follow up) 2.55 ± 0.9
NYHA score 0.35 ± 0.55
Number of hospitalizations 1.0 ± 1.26
Number of attacks of AHF 0.57 ± 0.98
SBP (mmHg) 98.45 ± 15.9
DBP (mmHg) 65.25 ± 9.7
Diagnosis:Ischemic      nNon-ischemic HF 53 (46.9%) 60 (53.1%)
Mortality 15 (13.2%)

Comparison of the parameters between the group of patients who died and the survived ones

Parameters Survived n=98 M ± SD Dead n=15 M ± SD P =
Weight – zero time (kg) 77.86 ± 12.55 76.46 ± 9.93 0.68
Weight – end of follow up 72.54 ± 11.74 69.33 ± 11.65 0.32
Htc – zero time (vol%) 0.396 ± 0.5 0.402 ± 0.4 0.64
Htc end of follow up 0.377 ± 0.5 0.366 ± 0.4 0.49
Scr (μmol/l) 84.47 ± 8.41 88.96 ± 6.11 0.49
Alb (g/l) 44.28 ± 2.67 43.56 ± 4.73 0.39
Tlip (g/l) 8.82 ± 1.22 8.84 ± 1.24 0.96
HDL(mmol/l) 1.22 ± 0.89 1.14 ± 0.22 0.74
LDL (mmol/l) 3.47 ± 0.63 3.47 ± 0.66 0.98
Tg (mmol/l) 1.55 ± 0.47 1.60 ± 0.55 0.70
Na (mmol/l) 141.82 ± 2.45 140.65 ± 3.52 0.10
K (mmol/l) 4.55 ± 0.43 4.80 ± 0.40 0.04
EF% zero time 36.39 ± 7.07 34.13 ± 5.57 0.23
EF% end of follow up 38.16 ± 7.86 31.53 ± 8.74 0.003
ΔEF% 1.74 ± 6.26 2.60 ± 8.82 0.02
N o Hospitalizations 0.86 ± 1.00 1.86 ± 1.50 0.001
No. AHF 0.40 ± 0.71 1.60 ± 1.63 0.000004
NYHA-FC zero 3.16 ± 0.71 3.93 ± 0.25 0.00007
NYHA-FC end 2.33 ± 0.75 3.93 ± 0.25 0.00000
NYHA score 0.25 ± 0.50 1.00 ± 0.37 0.000000
SBP (mmHg) 104.83 ± 15.21 82.30 ± 10.40 0.000000
DBP (mmHg) 68.95 ± 9.04 54.44 ± 6.69 0.000000
Age 57.20 ± 8.72 58.33 ± 7.79 0.637

Comparison of outcome between the control and the therapy group

a) Mortality
CER EER RR 95%CI RRR% X 2 NNT
6/34 0.17 9/79 0.113 0.66 0.21 – 1.96 34% R=0.37 17.5
b) Combined outcome
CER EER RR 95%CI RRR% X 2 NNT
29/34 0.85 41/79 0.51 0.6 0.33 – 1.13 40% R=0.0008 3.03

Comparison of outcome between the control group and the Metoprolol subgroup

a) Mortality
CER EER RR 95%CI RRR% H 2 NNT
6/34 0.17 4/29 0.13 0.76 0.2 – 3.04 24% 0.68 25
b) Combined outcome
CER EER RR 95%CI RRR% X 2 NNT
29/34 0.85 20/29 0.68 0.80 0.38 – 1.72 20% 0.0007 5.8

Comparison of outcome between the control group and the Bisoprolol subgroup

a) Mortality
CER EER RR 95%CI RRR% X 2 NNT
6/34 0.17 3/24 0.12 0.70 0.16 – 3.12 30% 0.58 20
b) Combined outcome
CER EER RR 95%CI RRR% X 2 NNT
29/34 0.85 14/24 0.58 0.68 0.3 – 1.56 32% 0.022 3.7

Comparison of outcome between the control group and the Carvedilol subgroup

a) Mortality
CER EER RR 95%CI RRR% X 2 NNT
6/34 0.17 2/26 0.076 0.44 0.08 – 2.34 56% 0.22 11
b) Combined outcome
CER EER RR 95%CI RRR% X 2 NNT
29/34 0.85 14/26 0.53 0.62 0.28 – 1.43 38% 0.0079 3.1

Our study did not show a statistically significant difference for cardiovascular mortality when comparing conventional therapy with treatment with beta blockers (p = 0.37), but there was a 34% risk reduction for mortality which, on the other hand, is of clinical relevance.

Our results for mortality in patients with heart failure when treated with beta blockers are similar to those in the Cibis II study (treatment with Bisoprolol), Our therapy group showed a significant improvement in the combined outcome (p = 0.0008), RRR 40% and NNT 3.03, which is consistent mostly with the US Carvedilol Study where RRR% for the combined outcome was 38%,

In the analysis of the mortality and the combined outcome between the control group with each therapy subgroup separately, it appeared that the Metoprolol subgroup did not have a significant difference compared to the control group for mortality (p = 0.68) and RRR was 24%, but for the combined outcome, there was a statistically significant improvement (p = 0.0007), which is consistent with the MCD Study for Metoprolol where the mortality rate was also not significant (p = 0.69),

The Bisoprolol group also did not show a statistically significant difference for mortality compared to the control group (p = 0.58), RRR was 30%, but it showed a significant difference for the combined outcome (p = 0.02) and was RRR 32%. This result differed from the CibisII study where the difference for the mortality was statistically significant, but CibisII study included larger number of patients and lasted longer (two and a half years),

The Carvedilol subgroup compared to the control group did not show a significant difference in mortality (p = 0.220), but RRR was highest among all the subgroups, 56%, and there was also a significant reduction in the combined outcome (p = 0.007), RRR 38%, which was consistent with the US Carvedilol Study where the RRR for the combined outcome was 63% (p = 0.001),

  1. The meta-analysis of Chatterjee (BMJ, 2013) on the effect of beta-blockers showed that they reduced the mortality in heart failure patients, but as a result of their class effect.
  2. No specific beta blocker showed predominant effect upon risk reduction of mortality in chronic heart failure patients,
  3. In conclusion, our study confirmed that patients with stable chronic heart failure, treated with optimal doses of beta-blockers, had a significant reduction of the risk from death as well as the combined outcome (death and/or number of hospitalizations).

No specific beta-blocker surpasses the effect of the other beta-blockers in the treatment of chronic heart failure considering the risk reduction. Competing Interests: The authors have declared that no competing interests exist.1. Eriksson H. Heart failure:a growing public health problem.

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  6. Benefits of Beta blockers in patients with heart failure and reduced ejection fraction:network meta-analysis.

BMJ.2013; 346 :f355. PMid:23325883 PMCid:PMC3546627. : The Impact of Treatment with Beta-Blockers upon Mortality in Chronic Heart Failure Patients

Can beta-blockers improve heart function?

Why it is important to do this review – Heart failure is the most rapidly growing cardiovascular condition globally ( Fonseca 2006 ; Heidenreich 2013 ; Ziaeian 2016 ). Substantial increases in heart failure prevalence are expected in the near future ( Heidenreich 2013 ; Schocken 2008 ).

An analysis from Scotland predicted that if the current trends in heart failure prevalence and mortality persists, an increase in prevalence of 17% in women and 31% in men will exist by the year 2020 ( Stewart 2003 ). If the above‐mentioned changes become reality, heart failure is likely to have an even more profound economic impact with a subsequent rise in hospitalisations and outpatient visits ( Heidenreich 2013 ; Stewart 2003 ; Vos 2012 ).

An optimal treatment might reduce morbidity and mortality associated with heart failure. Current guidelines from ACCF/AHA recommend the use of beta‐blockers in all patients with reduced LVEF and heart failure corresponding to stage B or C, or both (ACCF/AHA) regardless of whether they are with or without a history of myocardial infarction (see Table 2 ) ( Dunlay 2014 ; Hunt 2009 ; Smith 2011 ; Yancy 2013 ), or in patients classified with mild to moderate heart failure (class II‐IV) according to NYHA (see Table 1 ) ( Chatterjee 2002 ; Hunt 2009 ; McMurray 2012 ; Yancy 2013 ).

Several randomised clinical trials that assessed the long‐term effects of beta‐blockers showed an improvement in systolic function and a reversal of cardiac remodeling ( Bristow 2000 ; Groenning 2000 ). These trials suggest that adding beta‐blockers to conventional treatment may result in an approximately 24% to 35% relative risk reduction in mortality, may improve heart failure symptoms, and may reduce the risk of heart failure hospitalisations regardless of age and sex ( Dargie 1999 ; Hjalmarson 1999 ; Kotecha 2016 ; Mazurek 2015 ; Packer 2001 ).

Beta‐blockers may also reduce the risk of arrhythmia, improve LVEF, improve symptoms of heart failure, and may control ventricular rate ( Chatterjee 2013 ; Dargie 2001 ). Several existing meta‐analyses have compared the effects of beta‐blockers versus placebo or no intervention in participants with heart failure.

These meta‐analyses showed that beta‐blockers were associated with a decreased risk of death, improved NYHA class, decreased hospitalisation rates, and improved some types of exercise tolerance tests ( Abdulla 2006 ; Al‐Gobari 2013 ; Brophy 2001 ; Chatterjee 2013 ; Doughty 1997 ; Heidenreich 1997 ; Kotecha 2016 ; Lechat 1998 ; McAlister 2009 ).

However, these meta‐analyses did not systematically assess the following

Trials irrespective of outcome, follow‐up duration, number of participants. Outcomes at several time points and take into account the variability in follow‐up. The validity of the evidence with GRADE ( Guyatt 2008 ).

This Cochrane Review will be the first to use Cochrane methodology to assess the effects of beta‐blockers in patients with heart failure.

What is the function of beta blockers?

Beta blockers work mainly by slowing down the heart. They do this by blocking the action of hormones like adrenaline. Beta blockers usually come as tablets. They are prescription-only medicines, which means they can only be prescribed by a GP or another suitably qualified healthcare professional. Commonly used beta blockers include:

atenolol (also called Tenormin) bisoprolol (also called Cardicor or Emcor) carvedilol labetalol (also called Trandate) metoprolol (also called Betaloc or Lopresor) propranolol (also called Inderal or Angilol) sotalol

Can beta-blockers worsen heart failure?

Major cardiac effects caused by beta blockade include the precipitation or worsening of congestive heart failure, and significant negative chronotropy.

Can beta-blockers make heart failure worse?

MINNEAPOLIS, MN- December 4, 2019 – Nearly six million Americans have heart failure, a leading driver of healthcare costs in the United States. The “stiff heart” heart failure variant accounts for about half of all cases, and the vast majority of such patients take beta-blocker medications despite unclear benefit from their regular use.

A new publication in ” JAMA Network Open ” links use of beta-blockers to heart failure hospitalizations among those with this common “stiff heart” heart failure subtype. Heart failure occurs when the heart cannot meet the body’s demands. About half of patients have heart failure characterized by a normal squeeze but impaired relaxation of the heart muscle from a “stiff heart.” This is also known as heart failure with preserved ejection fraction.

The other half of cases are due to a “weak heart” with an abnormal squeeze, also known as heart failure with reduced ejection fraction. Beta-blockers—medications that lower the heart rate and blood pressure—are strongly recommended in national guidelines for treatment of “weak heart” heart failure because of their clear benefit.

  1. A big problem with ‘stiff heart’ heart failure is that we don’t have effective medical therapies,” said co-author Timothy Plante, MD, an assistant professor of medicine at the Larner College of Medicine at the University of Vermont.
  2. So, instead, we use the same medications that work for ‘weak heart’ heart failure.

Because beta-blockers save lives in ‘weak heart’ heart failure, we assume they are also effective in ‘stiff heart’ heart failure patients—this assumption may be wrong.” Plante joined lead author Daniel Silverman, MD, a cardiology fellow and clinical instructor in medicine at the University of Vermont Medical Center and Larner College of Medicine and senior author Markus Meyer, MD, an associate professor of medicine at the University of Minnesota Medical School, and colleagues to analyze data from the National Institutes of Health-funded TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) study, a trial of the medication spironolactone in patients with “stiff heart” heart failure.

  1. About four out of five study participants were on beta-blockers.
  2. The researchers found beta-blocker use to be a risk factor for hospitalizations for heart failure among these patients with “stiff heart” heart failure.
  3. Beta-blocker use was associated with a 74% higher risk of heart failure hospitalizations among participants with heart failure and a normal pump function,” Meyer said.

Despite their common use, the authors note that beta-blocker use in “stiff heart” heart failure has not been sufficiently studied. This publication extends their prior work, which found that halting beta-blockers markedly improves levels of the heart failure blood test known as BNP among patients with “stiff heart” heart failure.

In ‘stiff heart’ heart failure, the heart is less able to relax and fill with blood. Beta-blockers appear to increase pressures inside the heart. This may lead to symptoms like worsening shortness of breath and retention of fluid,” Silverman said. “Even people without heart failure will have more shortness of breath and less exercise capacity.

This has been a known class side effect for decades,” Meyer said. “It is important to understand that our findings are not proof that beta-blockers are harmful among patients with ‘stiff heart’ heart failure—it is just a concerning signal.” They believe their findings warrant a clinical trial to evaluate the safety and effects of beta-blockers in patients with “stiff heart” heart failure.

There are some big next steps, like reproducing this finding in other studies and testing if there is a benefit of stopping beta-blockers in patients with ‘stiff heart’ heart failure,” Silverman said. About the University of Minnesota Medical School The University of Minnesota Medical School is at the forefront of learning and discovery, transforming medical care and educating the next generation of physicians.

Our graduates and faculty produce high-impact biomedical research and advance the practice of medicine. Visit med.umn.edu to learn how the University of Minnesota is innovating all aspects of medicine. Contact: Kelly Glynn Media Relations Coordinator, University of Minnesota Medical School [email protected] 612-301-3273

Which drug should be avoided in heart failure?

Avoid taking –

Non-steroidal anti-inflammatory drugs (NSAIDS). These include: ibuprofen, Advil, Motrin, Aleve, Toradol, Celebrex. These medicines hold fluid and cause swelling. They also can harm your kidneys. Cold and cough medicines with pseudoephedrine or phenylephrine. Check with your doctor before using a cold medicine. Alka-Seltzer® – this has too much sodium (salt). Calcium channel blockers such as diltiazem (Cardizem) or verapamil (Calan, Verelan). These lessen the heart’s ability to pump if you have systolic heart failure. They may be used if you have diastolic heart failure or hypertrophic cardiomyopathy. Before you take any medicine, herb, or supplement, call your doctor.

Which patients should not receive beta-blockers?

When beta blockers are used – Beta blockers aren’t recommended as a first treatment in people who have only high blood pressure. Beta blockers aren’t usually prescribed for high blood pressure unless other medications, such as diuretics, haven’t worked well.

  • Irregular heart rhythm (arrhythmia)
  • Heart failure
  • Chest pain (angina)
  • Heart attacks
  • Migraine
  • Certain types of tremors

Your doctor may prescribe beta blockers along with other medications.