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Therapeutic Role of Beta-blockers in Hypertension:A Pragmatic Reappraisal
  JOHTN
THERAPEUTIC UPDATE
Therapeutic Role of Beta-blockers in Hypertension:
A Pragmatic Reappraisal
Soumitra Kumar
Professor and Head
Department of Cardiology, Vivekananda Institute of MedicalSciences, Kolkata, West Bengal, India
Correspondence: Soumitra Kumar, Professor andHead, Department of Cardiology, Vivekananda Instituteof Medical Sciences, Kolkata, West Bengal, India
Phone: +919831032519
e-mail: dr.soumitrakumar@gmail.com
 
ABSTRACT
Beta-blockers have been used as first-time antihypertensivesfor decades and such use has also been recommended byguidelines. However, subsequently some meta-analysesquestioned this status of beta-blockers by bringing to light theirlimitation in terms of stroke prevention and their metabolic sideeffects.Following this, several major international hypertensionguidelines have removed beta-blockers from the first line ofrecommended drugs. Some other guidelines, however, haveretained them as first-line antihypertensive. Age is an importantdeterminant of choice of antihypertensives and beta-blockershave proven to be very useful in young hypertensives especiallyif overweight. Amidst these controversies, vasodilatorybeta-blockers have emerged with a new promise. They arepotent antihypertensives with better reduction of central aorticpressure and a neutral or favorable metabolic profile.
Keywords: Age, Metabolic effects, Stroke, Vasodilatory.
How to cite this article: Kumar S. Therapeutic Role of Betablockersin Hypertension: A Pragmatic Reappraisal. HypertensJ 2016;2(2):80-85.
Source of support: Nil
Conflict of interest: None
 
 
INTRODUCTION

The concept of adrenergic blockade can be traced tothe work of Ahlquist1 when he described two discretetypes of adrenergic receptors, classified as alpha andbeta receptors. Later, James Black2 in his work reportedtwo non-selective beta-blockers pronethalol, with anendogenous sympathomimetic action, and propranolol,without such action for which he received the NobelPrize for Medicine and Physiology in 1988. Pronethalolwas discarded as carcinogenic but propranolol went onto become standard therapy for angina and arrhythmias.Later, propranolol became accepted as an oral antihypertensivemedication. In 1967, Lands et al3 described twotypes of beta-receptors, beta1 and beta2. Practolol was describedas the first beta1-selective blocker in 1970, but after 4 years of clinical use,4 it was abandoned on grounds ofsevere toxicity. In the following years, more non-selectivebeta-blockers (nadolol, timolol), beta1-selective blockers(atenolol, metoprolol, betaxolol, bisoprolol), beta-blockerswith an endogenous sympathomimetic action (pindolol,oxprenolol, caliprolol), and alpha/beta blocker (labetalol)emerged.

In more recent years, newer beta-blockers with vasodilatoryproperties, such as carvedilol and nebivolol, haveemerged. Carvedilol is a non-selective adrenergic blockerwith both alpha1 and beta1,2 receptor-blocking actions anda consequent direct vasodilatory effect.5 Nebivolol is abeta-blocker with high selectivity for beta1 receptors butwithout any intrinsic sympathomimetic action.6 It has anunique property of promoting endothelial production ofnitric oxide (NO), thus causing vasodilation. The newervasodilatory beta-blockers have the promise to provideseveral pleiotropic benefits beyond blood pressure control.

  Following the introduction of propranolol in 1976,beta-blockers have been widely used for the treatmentof systemic hypertension for around 40 years. However,some recent meta-analyses have suggested that they aresignificantly inferior to other classes of antihypertensives[thiazide diuretics, calcium channel blockers, angiotensinconvertingenzyme (ACE) inhibitors, angiotensin-IIreceptor blocker]. Based on this, some internationalhypertension guidelines have demoted beta-blockersto the fourth-line amongst antihypertensive drugs. Theclinical trials and meta-analyses which have had an effecton such clinical practice guidelines are reviewed below.

CLINICAL TRIALS OF BETA-BLOCKERS
IN HYPERTENSION


The major clinical studies which have been included inmost of the meta-analyses on use of beta-blockers are asfollows:
  • One trial with propranolol (MRC: Medical ResearchCouncil trial)
  • One trial with oxprenolol (IPPSH: International ProspectivePrimary Prevention Study in Hypertensives)
  • Two trials with pindolol (STOP-Hypertension: SwedishTrial in Old Patients with Hypertension and STOP-2:Swedish Trial in Old Patients with Hypertension-2)
  • Six trials with metoprolol (HAPPHY: Heart AttackPrimary Prevention in Hypertension; MAPHY: Metoprolol Atherosclerosis Prevention in Hypertensives;STOP-Hypertension; STOP-2; CAPP: CaptoprilPrimary Prevention Project; AASK: African AmericanStudy of Kidney Disease and Hypertension)
  • Thirteen trials with atenolol (HEP: Hypertension inElderly Patients with Primary care; HAPPHY; STOPHypertension;STOP-2; MRC; CAPP; UKPDS: UKProspective Diabetes Study; AASK; ELSA: EuropeanLacidipine on Atherosclerosis; LIFE: LosartanIntervention for Endpoint Reduction in Hypertension;INVEST: International Verapamil TrandolaprilStudy; CONVINCE: Controlled Onset VerapamilInvestigation of Cardiovascular End Points; ASCOTBPLA:Anglo-Scandinavian Cardiac Outcomes Trial -Blood Pressure Lowering Arm)

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Therapeutic Role of Beta-blockers in Hypertension: A Pragmatic Reappraisal

No trials till date have been carried out with vasodilatingbeta-blockers in hypertension.

Some of the more noteworthy trials are discussedbelow:

In the HAPPHY trial,7 diuretics (bendrofluazide orhydrochlorothiazide) have been compared with betablockers(metoprolol or atenolol) in 6,569 patients agedfrom 40 to 64 years for coronary events and deaths.There were no significant differences in the endpointsbetween the two groups of drugs. The MAPHY trial8was a follow-up extension of HAPPHY trial. The followupmedian time was 4.2 years, and the results indicateda lower total and cardiovascular mortality in the grouptaking beta-blockers.

In the UKPDS trial,9 1,148 hypertensive patients withtype 2 diabetes mellitus were allocated to a tight control ofBP using either captopril or atenolol. In this small samplesize, both treatments were equally effective in reducingBP and also equally effective in reducing macrovascularendpoints, deaths, myocardial infarction (MI), and stroke.

In the INVEST trial,10 the largest trial that investigatedbeta-blockers, 22,576 patients with hypertension andcoronary artery disease were randomized to a calciumantagonist strategy or atenolol. Trandolapril and/orhydrochlorothiazide were added to reach the target BPof 140/90 or 130/85 (for diabetic subjects). The atenololbasedstrategy was as effective as the calcium channelblocker-based strategy for preventing cardiac eventsand stroke.

In the LIFE trial,11 9,193 patients with hypertensionand left ventricular hypertrophy and average age of66 years were randomized to an atenolol-based strategyor a losartan-based strategy. Despite similar BP reduction,there was a greater reduction in cardiovascular endpoints(MI, stroke, and death) in the group taking losartan.

In the CONVINCE trial,12 16,602 hypertensive patientswere randomized either to controlled-release verapamilor to either hydrochlorothiazide or atenolol. Effectiveness of the calcium channel blocker in reducing cardiovasculardisease was similar but not better than a diuretic or betablocker-based treatment.In the ASCOT-BPLA trial,13 an antihypertensiveregimen based on amlodipine with perindopril wascompared to a regimen based on atenolol with bendroflumethazideand potassium as required. There was astatistically significant lowering in fatal and nonfatalstrokes, total cardiovascular events and procedures, andall cause mortality in the amlodipine-perindopril group.

The Conduit Artery Function Evaluation (CAFE)substudy14 of ASCOT-BPLA trial assessed central aorticpressure indirectly and amlodipine-based strategy wasassociated with lower central BP compared with atenololbasedtherapy group.

 
META-ANALYSES OF STUDIES
WITH BETA-BLOCKERS


Messereli et al15 conducted the first meta-analysis ofstudies in 1998 comparing the use of beta-blockers withdiuretics in an elderly (≥ 60 years of age) hypertensivepopulation (8,217 patients). Both treatment groupsreduced cerebrovascular events but beta-blockers did notreduce coronary events or mortality. Overall conclusionwas that beta-blockers should not be used as first-linetherapy in elderly patients any longer.

In 2001, a much larger meta-analysis comprising62,605 patients conducted by Staessen et al16 includeddiuretics, beta-blockers, calcium channel blockers, andACE inhibitors. All agents had similar long-term efficacyand safety, but the results of beta-blockers and diureticswere analyzed together.

Lindholm et al17 reported a larger meta-analysis of13 trials that compared beta-blockers with other treatments(105,951 subjects) and 7 trials that compared beta-blockerswith placebo or no treatment in 27,433 patients. In thefirst arm, there was an increased risk of stroke with betablockerscompared with other antihypertensive agents.Beta-blockers (predominantly atenolol) reduced the risk ofstroke in the placebo-controlled trials but only by 50% ofwhat was expected with other agents. No trial comparedthe use of atenolol with other beta-blockers.

Law et al18 conducted the largest meta-analysis comparingdifferent classes of BP lowering drugs in 464,000patients. According to this analysis, five main classesof antihypertensive agents (thiazide, calcium channelblockers, beta-blockers, angiotensin receptor blockers,and ACE inhibitors) showed similar efficacy within a fewpercentage points in preventing coronary heart diseaseand stroke.

Most recent meta-analysis is an update by Kuyperand Khan19 of a previous meta-analysis by Khanand McAlister.20 Conclusion of a large meta-analysis comprising 145,811 participants from 21 hypertensiontrials concluded that the use of beta-blockers in youngerpatients is advisable since it is associated with significantreduction in cardiovascular morbidity and mortalitybut they should not be considered first-line therapy inolder patients. The updated meta-analysis was uniquein the sense that the authors sought to compare efficacyof atenolol vs non-atenolol beta-blockers and alsostratified patients according to age. They concluded thatboth atenolol and non-atenolol beta-blockers decreasecardiovascular endpoints in young patients, suggestingthat age is a more important factor in the selection ofantihypertensive, and type of beta-blocker chosen may beless important. The authors also concluded that whethersignificantly worse outcome in older hypertensivesis a class effect of beta-blockers or specific to atenololremains unclear. Whether lack of lowering of central BPin elderly population as reported by CAFE study14 canbe attributed as an explanation remains a hypothesis.The possibility that metabolic effects of non-vasodilatingbeta-blockers may also be responsible has been suggestedby the authors, but hard outcomes studies are requiredto prove this.
 
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Soumitra Kumar

USE OF BETA-BLOCKERS IN COMPELLING
INDICATIONS


Coronary artery disease: Beta-blockers are recommendedby several guidelines for use in hypertensive patientswith coronary artery disease because they reduce bloodpressure, heart rate, and myocardial oxygen demand; asa consequence, they reduce ischemia.21,22 Effects of nonvasodilatingbeta-blockers on coronary blood flow arevariable. Vasodilatory beta-blockers have the potentialto improve coronary blood flow at rest and also duringexercise so that they can be a better option than traditionalbeta-blockers; however, currently vasodilating betablockersare not recommended by use in chronic stableangina.

Postmyocardial infarction: Valuable role of beta-blockers inpatients after MI has been established by several trials(BHAT, the Gothenburg Metoprolol trial, the NorwegianTimolol trial, CAPRICORN)23-26 and accordingly it iscompelling to use beta-blockers in hypertensive patientsfollowing MI.21,22

Heart failure: Several meta-analyses of beta-blocker trialshave conclusively established that beta-blocker use resultsin a consistent 30% reduction in mortality, 40% reductionin hospitalization, and 38% reduction in suddencardiac death in patients with chronic heart failure.27,28Another meta-analysis reported that 26 patients wouldneed to be treated to avoid one death.29 Bisoprolol,metoprolol succinate, and carvedilol are approved for usein hypertensive patients with chronic systolic heart failure.In the SENIORS trial, nebivolol was shown to reduce thecomposite risk of all-cause mortality or cardiovascularrelatedhospital admission by 14% compared to placebo(p = 0.039), but not all-cause mortality alone.30 It is notcurrently approved for use in heart failure indication.
 
AGE AND CHOICE OF BETA-BLOCKERS
AS ANTIHYPERTENSIVES


The Framingham Heart Study showed that in youngersubjects, diastolic blood pressure was the prime predictorof cardiovascular events, shifting to systolic bloodpressure and then pulse-pressure with increasing age.31This effect was particularly evident in overweight/obesesubjects.32 Such young subjects have a high adrenergicdrive and cardiac output, and first-line beta-blockadehas performed well in such patients, both in terms ofcontrolling blood pressure and in preventing MI.33-35 Incomparison, first-line beta-blockade (mainly atenolol)has performed poorly in reducing cardiovascular riskin elderly hypertensives. Reasons may be attributedto metabolic disturbances that may be evoked, lack ofimprovement of vascular compliance, or lack of effect oncentral aortic pressure, or poor reversal of left ventricularhypertrophy. Beta-blocker-induced bradycardia maynot work beneficially in all hypertensive patients. Thisparadox has to do with the reflected pulse wave. Ideallythe reflected wave that should reach the heart is diastoleand augment diastolic filling. If it returns earlier duringthe cardiac cycle it amplifies the outgoing pressurewave, i.e., worsens augmentation index and raisescentral aortic pressure. This phenomenon especiallyresults from the combination of beta-blocker-inducedbradycardia in elderly patients with "stiff" arteries andit is termed "pseudo-antihypertensive effect."36 However,not all pharmacological effects of beta-blockers in theelderly are undesirable. Elderly patients, unlike theiryounger counterparts, experience a decreased pulsepressureon standing. This effect is offset and turnedinto a "paradoxic" pressor effect by long-term betablockertreatment and this may protect the elderly fromorthostatic symptoms.37

ARE VASODILATING BETA-BLOCKERS
DIFFERENT?


Vasodilatory beta-blockers by causing peripheralvasodilation reduce cardiac preload and afterload.Thus, they reduce blood pressure by reducing systemicvascular resistance while maintaining cardiac output.38,39Vasodilatory beta-blockers are also devoid of any adverseeffect on lipid and glucose metabolism and they can reverse arterial remodeling. Remodeled (Stiff) arteriesincrease distal wave reflection of blood back to the aorta,which augment central systolic pulse wave emanatingfrom the heart to increase central aortic pressure. Thus,vasodilatory beta-blockers have the potential to lowercentral aortic pressure.38

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Therapeutic Role of Beta-blockers in Hypertension: A Pragmatic Reappraisal

Vasodilatory beta-blockers that are currently inclinical use are labetalol, carvedilol, and nebivolol.Labetalol and carvedilol are non-selective beta-blockerswith alpha1 receptor-blocking activity and minimal(labetalol) or no (carvedilol) intrinsic sympathomimeticactivity.38,39 Nebivolol is a high beta1-selectiveblocker that does not have alpha1-blocking activityor intrinsic sympathomimetic activity.38,39 Nebivololmediates endothelium-dependent vasodilatation viathe L-arginine-nitric oxide (NO)-dependent pathway.The combination of beta-adrenoceptor antagonism andNO-mediated vasodilatation not only potentiates theblood pressure activity of nebivolol but also confers abroader and favorable metabolic profile.40 Nebivolol notonly significantly reduces central aortic pressure alongwith brachial pressure but also significantly reduces augmentationindex and carotid-femoral pulse wave velocity,both being independent cardiovascular risk markers.41 Interms of control of blood pressure, a meta-analysis of 12randomized clinical trials in patients with hypertensionhas shown that nebivolol was superior to ACE inhibitorsand comparable to other beta-blockers, calcium channelblockers, and losartan.42

WHAT IS THE CURRENT ROLE OF BETA-
BLOCKERSIN TREATING HYPERTENSION?


Despite exclusion of beta-blockers as first-line drugs insome leading international guidelines of hypertension,43-45some other guidelines like European and CanadianHypertension Guidelines have retained beta-blockersas one of the five first-line antihypertensive drugs.46,47Major reasons accounting for relegation of beta-blockersfrom first line are their failure to reduce stroke incidenceand their adverse metabolic profile, especially causationof new-onset diabetes mellitus. However, guidelinesthat have retained them rate beta-blockers very effectivein young hypertensives, especially in overweightindividuals. All guidelines, however, express concurrencein terms of indispensability of beta-blockers in somecompelling indications like hypertension in patientssuffering from angina, heart failure, and post-MI.

Amidst the controversy involving beta-blockers, inrecent times, vasodilatory beta-blockers have emergedwith a new promise. Whereas, they lower bloodpressure to a similar degree as other antihypertensivedrugs, they may provide better central aortic pressure reductions compared to traditional beta-blockers andare also associated with neutral or favorable metaboliceffects. There is, however, lack of data comparing hardcardiovascular outcomes between vasodilating and nonvasodilatingbeta-blockers in hypertension.
 
It is unlikely that there will be a single first-line drugfor hypertensives as most patients will eventually needmultiple drugs to control their blood pressure. Treatmentneeds to be individualized for all patients. Chronicregular use of beta-blockers has been associated withdetrimental effects including an increase in asthmarelateddeaths. However, more recent data48 suggestthat certain beta-blockers, specifically beta-adrenoceptorinverse agonists (e.g., nadolol), may be useful in chronictreatment of asthma by inhibiting constitutive or ligandinducedactivation of this pathway. Choice of treatmentshould not only be dictated by underlying cardiovascularrisk factors and potential adverse effects, but also by theage of the patient and his/her co-morbidities. In thatscenario, beta-blockers, especially its newer vasodilatoryversions, will continue to be an integral part of ourantihypertensive regime.

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