P . b . b . 0 2 Z 0 3 1 1 0 5 M , V e r l a g s p o s t a m t : 3 0 0 2 P u r k e r s d o r f , E r s c h e i n u n g s o r t : 3 0 0 3 G a b l i t z

Krause & Pachernegg GmbHVerlag für Medizin und WirtschaftA-3003 Gablitz

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"Herzinsuffizienz"

Satellitensymposium bei der

Jahrestagung 2001; der

Österreichischen

Kardiologischen Gesellschaft

Linz, 25. Mai 2001

Update on Beta-Blockers in Congestive Heart

Failure

Waagstein F

Journal für Kardiologie - Austrian Journal

of Cardiology 2001; 8 (Supplementum D), 5-6

LebensbedrohLich doch oft übersehen.1

Die Diagnose von Transthyretin-Amyloidose mit Kardiomyopathie (ATTR-CM) erfolgt in vielen Fällen erst verzögert oder wird gänzlich übersehen.

HFpEF*: bei Patienten, die typischerweise übeR 60 JAhRe alt sind2

INTOLERANZ: gegenüber Herzinsuffizienzbehandlung wie z.b.: ACe-hemmer oder beta blocker3

DISKREPANZ: zwischen Niedervoltage und erhöhter linksventrikulärer Wanddicke4

HEART FAILURE WITH PRESERVED EJECTION FRACTION in pat ients typ ica l l y over 60 1-3

INTOLERANCE to s tandard hear t fa i lu re therap ies , such as ang io tens in-conver t ing enzyme inh ib i to rs , ang io tens in receptor b lockers , and beta b lockers 7-9

DISCORDANCE between QRS vo l tage on e lect rocard iography (ECG) and le f t vent r icu la r (LV ) wa l l th ickness seen on echocard iography 10,11

D iagnos is o f CARPAL TUNNEL SYNDROME or LUMBAR SPINAL STENOSIS8,14 ,16-22

Echocard iography showing INCREASED LV WALL THICKNESS2,13 ,22 ,25 ,26

AUTONOMIC NERVOUS SYSTEM dysfunction, inc lud ing gast ro in tes t ina l compla in ts or unexp la ined we ight loss 2,22,27 ,28

HEART FAILURE WITH PRESERVED EJECTION FRACTION in pat ients typ ica l l y over 60 1-3

INTOLERANCE to s tandard hear t fa i lu re therap ies , such as ang io tens in-conver t ing enzyme inh ib i to rs , ang io tens in receptor b lockers , and beta b lockers 7-9

DISCORDANCE between QRS vo l tage on e lect rocard iography (ECG) and le f t vent r icu la r (LV ) wa l l th ickness seen on echocard iography 10,11

D iagnos is o f CARPAL TUNNEL SYNDROME or LUMBAR SPINAL STENOSIS8,14 ,16-22

Echocard iography showing INCREASED LV WALL THICKNESS2,13 ,22 ,25 ,26

AUTONOMIC NERVOUS SYSTEM dysfunction, inc lud ing gast ro in tes t ina l compla in ts or unexp la ined we ight loss 2,22,27 ,28

HEART FAILURE WITH PRESERVED EJECTION FRACTION in pat ients typ ica l l y over 60 1-3

INTOLERANCE to s tandard hear t fa i lu re therap ies , such as ang io tens in-conver t ing enzyme inh ib i to rs , ang io tens in receptor b lockers , and beta b lockers 7-9

DISCORDANCE between QRS vo l tage on e lect rocard iography (ECG) and le f t vent r icu la r (LV ) wa l l th ickness seen on echocard iography 10,11

D iagnos is o f CARPAL TUNNEL SYNDROME or LUMBAR SPINAL STENOSIS8,14 ,16-22

Echocard iography showing INCREASED LV WALL THICKNESS2,13 ,22 ,25 ,26

AUTONOMIC NERVOUS SYSTEM dysfunction, inc lud ing gast ro in tes t ina l compla in ts or unexp la ined we ight loss 2,22,27 ,28

HEART FAILURE WITH PRESERVED EJECTION FRACTION in pat ients typ ica l l y over 60 1-3

INTOLERANCE to s tandard hear t fa i lu re therap ies , such as ang io tens in-conver t ing enzyme inh ib i to rs , ang io tens in receptor b lockers , and beta b lockers 7-9

DISCORDANCE between QRS vo l tage on e lect rocard iography (ECG) and le f t vent r icu la r (LV ) wa l l th ickness seen on echocard iography 10,11

D iagnos is o f CARPAL TUNNEL SYNDROME or LUMBAR SPINAL STENOSIS8,14 ,16-22

Echocard iography showing INCREASED LV WALL THICKNESS2,13 ,22 ,25 ,26

AUTONOMIC NERVOUS SYSTEM dysfunction, inc lud ing gast ro in tes t ina l compla in ts or unexp la ined we ight loss 2,22,27 ,28

HEART FAILURE WITH PRESERVED EJECTION FRACTION in pat ients typ ica l l y over 60 1-3

INTOLERANCE to s tandard hear t fa i lu re therap ies , such as ang io tens in-conver t ing enzyme inh ib i to rs , ang io tens in receptor b lockers , and beta b lockers 7-9

DISCORDANCE between QRS vo l tage on e lect rocard iography (ECG) and le f t vent r icu la r (LV ) wa l l th ickness seen on echocard iography 10,11

D iagnos is o f CARPAL TUNNEL SYNDROME or LUMBAR SPINAL STENOSIS8,14 ,16-22

Echocard iography showing INCREASED LV WALL THICKNESS2,13 ,22 ,25 ,26

AUTONOMIC NERVOUS SYSTEM dysfunction, inc lud ing gast ro in tes t ina l compla in ts or unexp la ined we ight loss 2,22,27 ,28

HEART FAILURE WITH PRESERVED EJECTION FRACTION in pat ients typ ica l l y over 60 1-3

INTOLERANCE to s tandard hear t fa i lu re therap ies , such as ang io tens in-conver t ing enzyme inh ib i to rs , ang io tens in receptor b lockers , and beta b lockers 7-9

DISCORDANCE between QRS vo l tage on e lect rocard iography (ECG) and le f t vent r icu la r (LV ) wa l l th ickness seen on echocard iography 10,11

D iagnos is o f CARPAL TUNNEL SYNDROME or LUMBAR SPINAL STENOSIS8,14 ,16-22

Echocard iography showing INCREASED LV WALL THICKNESS2,13 ,22 ,25 ,26

AUTONOMIC NERVOUS SYSTEM dysfunction, inc lud ing gast ro in tes t ina l compla in ts or unexp la ined we ight loss 2,22,27 ,28

Achten sie Auf diese hinweise:

* heart failure with preserved ejection fraction

Pfizer Corporation Austria GmbH, Wien, www.pfizer.at

Referenzen: 1. Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a pro-spective, observational cohort study. Circulation. 2016;133(3):282-290. 2. Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. 3. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003. 4. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13. PP-VYN-AUT-0207/01.2020

Pfizer Corporation Austria GmbH, Wien, www.pfizer.at

www.verdAchtunddiAgnose.At - hier erfahren sie mehr über Attr-cM.

DIAGNOSE: eines Karpaltunnelsyndroms oder einer Lumbalstenose1,3

ECHOKARDIOGRAPHIE: hypertrophie des linken Ventrikels2

NERVENSYSTEM: Dysfunktion des autonomen Nervensystems einschließ-lich von gastrointestinalen beschwerden und unerklär-barem Gewichtsverlust2

5J KARDIOL SUPPL D/2001

INTRODUCTION

Beta-blockers which were earlierconsidered to be pure negative ino-tropic drugs have until recently beencontraindicated for treatment of con-gestive heart failure. This has beenthe case despite the fact that the con-cept presented more than 25 yearsago as an option for treatment in idio-pathic dilated cardiomyopathy withtachycardia later followed by severalsmall long-term studies confirmingtheir ability to improve cardiac func-tion and reduce symptoms. The origi-nal rationale for the concept was res-toration of myocardial energy balanceby reducing cardiac work, mainly bynormalizing heart rate. This hypoth-esis has been confirmed later in clini-cal and experimental studies but sev-eral other mechanisms seem to play arole, such as interaction with otherneurohormones, restoration of imbal-ance between vagal and sympatheticinnervation of the heart, reduction ofapoptosis and oxidative stress leadingto slower disease progression andrestoring electrical stability implyinglower risk of sudden death.

Three large placebo-controlledrandomised trials have now finallyproven that three different beta-blockers, on top of ACE-inhibitors,reduce both cardiovascular morbi-dity and mortality in mild, moderateand severe heart failure.

EFFECT ON CARDIAC FUNCTIONAND EXERCISE CAPACITY

Numerous controlled studies haveconsistently shown improvement inejection fraction, which exceeds thecombined effects of digoxin and ACE-inhibitors. Diastolic function is im-proved similarly and preceeds im-provement in systolic function. Re-versed remodelling has been shownboth with metoprolol and carvediloloccuring after 6 months of treatmentand seems to be greater than withACE-inhibitors alone. The effect onexercise capacity is less clear but theremay be a somewhat better effect withthe beta1-selective blocker metoprololcompared to the non-selective beta-blockers carvedilol and bucindolol.This may be a consequence of lessreduction of peak exercise heart ratewith metoprolol possibly related toupregulation of beta-adrenergicreceptors by metoprolol in contrast toabsence of upregulation withcarvedilol and bucindolol.

EFFECT ON MORBIDITYAND MORTALITY

Three large prospective randomisedsurvival trials have now consistentlyshown a reduction in mortality by 34–35 % [1–3] (Figs. 1, 2, table 1). Twotrials, CIBIS II and COPERNICUS, us-

ing bisoprolol and carvedilol includedonly more severely ill patients inNYHA class III–IV, whereas the MERIT-HF trial also included NYHA class IIpatients. All studies showed reductionof cardiovascular morbidity [1, 4]reflected as fewer re-admissions tohospital for cardiovascular reasons aswell as fewer days in hospital. A retro-spective analysis from the CIBIS II andthe MERIT-HF trials using the sameinclusion criteria as in the COPER-NICUS trial, ejection fraction ≤ 0.25and NYHA class III and IV showedsimilar average ejection fraction andplacebo mortality indicating that thesesubsets of patients matched well thepatients included in the COPERNICUStrial. Moreover, reduction in mortalityin the MERIT-HF subset of patientswere of the same order as in theCOPERNICUS trial, 39 % vs 35 %, andfor morbidity all cause 25 % vs 20 %,for cardiovascular cause 32 % vs 28 %and for heart failure cause 44 % vs33 % indicating a strong benefit ofmetoprolol also in more severe heartfailure patients. A fourth trial [5] inpatients with severe heart failure (BEST),did not show a significant reduction inall-cause mortality, although a signifi-cant reduction in cardiovascular deathand heart transplantation or death wasobserved. The reason for discrepancybetween this trial and the other threetrials remains obscure, but too strongbeta2-blocking effect reducing nore-pinephrine release too markedly in themore severe heart failure patients hasbeen a proposed explanation [5].

F. Waagstein

UPDATE ON BETA-BLOCKERS INCONGESTIVE HEART FAILURE

UPDATE ONBETA-BLOCKERS

Figure 2: CIBIS-II: Survival curves. From [2] with permis-sion

Figure 1: Kaplan-Meier curves ofcumulativepercentage oftotal mortality(p value adjustedfor two interimanalyses). From[1] with permis-sion

For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH.

6 J KARDIOL SUPPL D/2001

HOW TO USE BETA-BLOCKERSIN CHFWhen initiating beta-blockade in con-gestive heart failure it is important tostart with a low dose and increase thedose slowly over 6–8 weeks in orderto allow the circulation to adapt toreduction of cardiac sympathetic drivecaused by blockade of myocardialbeta-adrenergic receptors. The startingdose ranges from 1/8 to 1/16 of thetarget dose depending on the severityof heart failure. Initial systolic bloodpressure should be ≥ 100 mmHg. Incase it is not, one should considerlowering the ACE-inhibitor dose inorder to obtain an appropriate bloodpressure allowing initiation of thebeta-blocker. A reduction in the ACE-inhibitor dose from target dose doesnot seem to reduce the effect on mor-tality significantly according to theATLAS study [6], whereas the strongbeneficial effect on mortality frombeta-blockade would be missed if thepatient does not receive a beta-blocker. The data base from all threebeta-blocker mega trials show clearlythat withdrawal of beta-blockade forcardiovascular reasons like bradycar-dia, hypotension or increase in con-gestive heart failure is rare since itoccurs as often or more frequently inthe placebo treated patients. This indi-cates a high degree of safety with thesedrugs. Also for adverse events relatedto respiratory disease, psychiatric dis-orders or diabetes no increase wasseen with metoprolol. As a rule, thefinal dose of beta-blockers should bethe target dose for these trials. If, how-ever, the final dose is lower than thetarget dose for reasons like hypoten-sion, bradycardia or marked fatigue,the lower dose would also significantlyreduce morbidity and mortality ac-cording to retrospective analysis ofMERIT-HF [7]. The subset of patientsnot tolerating a target dose of meto-prolol in that study were sicker thanthose tolerating the target dose, asreflected by a higher placebo mortal-ity. Despite this the withdrawal rate for

cardiovascular reasons, was evenmore markedly reduced by metoprololcompared to patients receiving thetarget dose. This indicates the impor-tance of trying to treat also these pa-tients since the high mortality rate inthis patient group implies that morelifes could be saved per treated patientyears than in patients with lower risk.

CONCLUSION

It can now be finally stated that beta-blockers should be given in addition toACE-inhibitors to all haemodynamical-ly stable patients with congestive heartfailure due to primarily systolic dys-function regardless of severity of dis-ease. Due to their effectiveness inNYHA class II as demonstrated withmetoprolol in the MERIT-HF trial it isimportant to start treatment as early aspossible after diagnosis to preventsudden death, which is the predomi-nant cause of death in NYHA class IIand III patients, as well as preventingprogression of disease into more se-vere heart failure. The common de-nominator for the beta-blockers usedin the three survival trials showingalmost identical effects on mortalityand morbidity, is beta1-adrenergicreceptor blockade, which raises thequestion whether beta2- and alpha1-blockade give additional benefit. Theexperience from the BEST trial withbucindolol emphazises that only beta-blockers proven to be beneficial incontrolled trials should be used fortreatment in heart failure.

References:1. MERIT-HF Study Group. Effect of meto-prolol CR/XL in chronic heart failure: Meto-

prolol CR/XL Randomised intervention Trialin Congestive Heart Failure (MERIT-HF).Lancet 1999; 353: 2001–7.2. CIBIS-II Investigators and Committees.The cardiac insufficiency bisoprolol study II(CIBIS-II): a randomised trial. Lancet 1999;353: 9–13.3. Packer M, Coats AJS, Fowler MB, KatusHA, Krum H, Mohacsi P, Rouleau JL,Tendera M, Castaigne A, Roecker EB,Schultz MK, DeMets DL. Effect of carvedilolon survival in severe chronic heart failure. NEngl J Med 2001; 344: 1651–8.4. Hjalmarson Å, Goldstein S, Fagerberg B,Wedel H, Waagstein F. et al. for the MERIT-HF Study Group. Effects of controlled-re-lease metoprolol on total mortality, hospi-talizations, and well-being in patients withheart failure. The metoprolol CR/Xl Rando-mized Intervention Trial in Congestive HeartFailure (MERIT-HF). JAMA 2000; 283, 1293–1302.5. The Beta-Blocker Evaluation Bucindololof Survival Trial Investigators. A trial of thebeta-blocker bucindolol in patients withadvanced chronic heart failure. N Engl JMed 2001; 344: 1659–67.6. Packer M, Poole-Wilson PA, ArmstrongPW, Cleland JG, Horowitz LD, Massie BM,Ryden L, Thygesen K, Uretsky BF. Compara-tive effects of low and high doses of theangiotensin-converting enzyme inhibitor,lisinopril, on morbidity and mortality inchronic heart failure. ATLAS Study Group.Circulation 1999; 100: 2312–8.7. Wikstrand J, Hjalmarson Å, Waagstein F,Fagerberg B, Goldstein S, Kjekshus J, WedelH for the MERIT-HF Study Group. Achievedmetoprolol CR/XL. Dose and clinical out-comes. Analyses of the experiences inMERIT-HF. Submitted.

Correspondence to:Prof. Finn Waagstein, M.D.Division of Cardiology andWallenberg Laboratory forCardiovascular ResearchSahlgrenska University HospitalGöteborg, SwedenE-mail: finn@wlab.wall.gu.se

Table 1: Overview: Effects of Metoprolol CR/XL on endpoints (MERIT-HF trial)Primary endpoints• Total mortality –34 % p = 0.0062• Total mortality or all cause hospitalization –19 % p = 0.0001Secondary endpoints• Total mortality or hospitalization due to worsening CHF –31 % p < 0.0001• Death or heart transplantation –32 % p = 0.0002• Cardiovascular mortality –38 % p < 0.0001• Sudden death –41 % p = 0.0002• Death from worsening CHF –49 % p = 0.0023Tertiary endpoints• Total mortality or hospitalization or

emergency department visit due to worsening CHF –32 % p < 0.0001

UPDATE ONBETA-BLOCKERS

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