Antiplatelet activity of β-blockers: new light on existing data
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Commentary Antiplatelet activity of β-blockers: new light on existing data Pietro Minuz, Stefano Calabria & Cristiano Fava Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy β-Adrenergic receptor blockers have been used success- fully for decades for the prevention of cardiovascular events in the setting of arterial hypertension and coronary artery disease. The biological plausibility of this protective activity is supported by the reduction in blood pressure and intrinsic adrenoreceptor-mediated cardiac effects, only indirectly related to thrombogenesis. Limited infor- mation is available concerning additional mechanisms that may contribute directly to the protective activity of individual β-blockers, or of the class as a whole, towards atherothrombosis. A flare of scientific investigation accompanied the development of β-blockers, aimed at defining their poten- tial as antiplatelet agents. In order to investigate the effects of individual β-blockers on platelet function, light transmission aggregometry (LTA) was mostly used, either to explore in vitro the effects of the tested compounds up to very high concentrations and ex vivo, in treated patients and healthy subjects. A series of small, but adequately designed clinical trials was generated in a time span of three decades. The systematic review and meta-analysis performed by Bonten et al. [1]. now summarizes the sparse, inconsistent information, including clinical studies in which LTA was used to examine platelet function as a surrogate end-point of an antithrombotic activity of different β-blockers. Converging evidence suggests that specific compounds actually inhibit ex vivo platelet aggregation, and that antiplatelet activity may not be regarded as a class effect. A substantial heterogeneity exists among β-blockers con- cerning their selectivity for the adrenergic receptors and the presence of specific biochemical characteristics, of rel- evance for the pharmacokinetic and pharmacodynamic properties, dictating a preferential use in the treatment of arterial hypertension, ischaemic heart disease, heart failure or noncardiovascular diseases. This may be the case also for the antiaggegatory activity observed with β-blockers. Of the tested compounds, particularly lipophilic and non- selective β-blockers display this activity [1]. Explanation of a clinical finding, however, necessitates preliminary mechanistic investigation. According to this proposition, several in vitro studies have shown that the antiplatelet activity of some β-blockers is independent of occupancy of β-adrenergic receptors, which are scarcely expressed on the platelet surface and do not transduce proaggregatory signals [2]. Propranolol in vitro, at concentrations similar to those achieved in vivo, raises the threshold dose for the platelet aggregatory response to adenosine diphosphate (ADP). At higher concentrations, a broarder spectrum of activities was identified; platelet adhesion, aggregation induced by different agonists and the release reaction were inhibited [3]. The effects of β-blockers on human platelets have been related to their liposolubility; for example, carvedilol, which is more lipophilic than propranolol, possibly by interacting with membrane macromolecules, produces a dose-dependent, adrenergic receptor-independent, antiplatelet effect [4, 5]. Carvedilol has additional antioxi- dant and vasodilator properties that may contribute to its efficacy in the treatment of heart failure [6]. However, neither the biochemical mechanisms nor the signalling pathways leading to inhibition of platelet activation have been investigated in detail. Recently, nebivolol was found in vitro to exert antiaggregatory effects, mediated by the release of nitric oxide in platelets, which translates into a blunted platelet-dependent thrombogenesis in experi- mental models [6, 7]. Some critical points should be considered concerning the methodology of meta-analyses dealing with studies of small sample size and/or using surrogate end-points. The overall quality (or risk of bias) of a meta-analysis is directly proportional to the quality of the primary studies [8]. Dis- tortion deriving from biased primary studies increases exponentially if surrogate end-points are used that are not well standardized, particularly if technically demanding and of limited use. Thus, the common criticism, applicable to all meta-analyses, i.e. ‘to combine apples with oranges’, could be considerably worsened when analysing platelet British Journal of Clinical Pharmacology DOI:10.1111/bcp.12438 Br J Clin Pharmacol / 78:5 / 937–939 / 937 © 2014 The British Pharmacological Society
Transcript of Antiplatelet activity of β-blockers: new light on existing data
Commentary
Antiplatelet activity of β-blockers: new light onexisting data
Pietro Minuz, Stefano Calabria & Cristiano Fava
Department of Medicine, Section of Internal Medicine, University of Verona, Verona, Italy
β-Adrenergic receptor blockers have been used success-fully for decades for the prevention of cardiovascularevents in the setting of arterial hypertension and coronaryartery disease. The biological plausibility of this protectiveactivity is supported by the reduction in blood pressureand intrinsic adrenoreceptor-mediated cardiac effects,only indirectly related to thrombogenesis. Limited infor-mation is available concerning additional mechanismsthat may contribute directly to the protective activity ofindividual β-blockers, or of the class as a whole, towardsatherothrombosis.
A flare of scientific investigation accompanied thedevelopment of β-blockers, aimed at defining their poten-tial as antiplatelet agents. In order to investigate theeffects of individual β-blockers on platelet function, lighttransmission aggregometry (LTA) was mostly used, eitherto explore in vitro the effects of the tested compounds upto very high concentrations and ex vivo, in treated patientsand healthy subjects. A series of small, but adequatelydesigned clinical trials was generated in a time span ofthree decades.
The systematic review and meta-analysis performed byBonten et al. [1]. now summarizes the sparse, inconsistentinformation, including clinical studies in which LTA wasused to examine platelet function as a surrogate end-pointof an antithrombotic activity of different β-blockers.Converging evidence suggests that specific compoundsactually inhibit ex vivo platelet aggregation, and thatantiplatelet activity may not be regarded as a class effect. Asubstantial heterogeneity exists among β-blockers con-cerning their selectivity for the adrenergic receptors andthe presence of specific biochemical characteristics, of rel-evance for the pharmacokinetic and pharmacodynamicproperties, dictating a preferential use in the treatment ofarterial hypertension, ischaemic heart disease, heart failureor noncardiovascular diseases. This may be the case alsofor the antiaggegatory activity observed with β-blockers.Of the tested compounds, particularly lipophilic and non-selective β-blockers display this activity [1].
Explanation of a clinical finding, however, necessitatespreliminary mechanistic investigation. According to thisproposition, several in vitro studies have shown that theantiplatelet activity of some β-blockers is independent ofoccupancy of β-adrenergic receptors, which are scarcelyexpressed on the platelet surface and do not transduceproaggregatory signals [2].
Propranolol in vitro, at concentrations similar to thoseachieved in vivo, raises the threshold dose for the plateletaggregatory response to adenosine diphosphate (ADP). Athigher concentrations, a broarder spectrum of activitieswas identified; platelet adhesion, aggregation induced bydifferent agonists and the release reaction were inhibited[3]. The effects of β-blockers on human platelets have beenrelated to their liposolubility; for example, carvedilol,which is more lipophilic than propranolol, possibly byinteracting with membrane macromolecules, producesa dose-dependent, adrenergic receptor-independent,antiplatelet effect [4, 5]. Carvedilol has additional antioxi-dant and vasodilator properties that may contribute to itsefficacy in the treatment of heart failure [6]. However,neither the biochemical mechanisms nor the signallingpathways leading to inhibition of platelet activation havebeen investigated in detail. Recently, nebivolol was foundin vitro to exert antiaggregatory effects, mediated by therelease of nitric oxide in platelets, which translates into ablunted platelet-dependent thrombogenesis in experi-mental models [6, 7].
Some critical points should be considered concerningthe methodology of meta-analyses dealing with studies ofsmall sample size and/or using surrogate end-points. Theoverall quality (or risk of bias) of a meta-analysis is directlyproportional to the quality of the primary studies [8]. Dis-tortion deriving from biased primary studies increasesexponentially if surrogate end-points are used that are notwell standardized, particularly if technically demandingand of limited use. Thus, the common criticism, applicableto all meta-analyses, i.e. ‘to combine apples with oranges’,could be considerably worsened when analysing platelet
British Journal of ClinicalPharmacology
DOI:10.1111/bcp.12438
Br J Clin Pharmacol / 78:5 / 937–939 / 937© 2014 The British Pharmacological Society
aggregation, in this specific case, or endothelial function,in another plausible scenario. When LTA is used as a quan-titative index of platelet response, standardized stimuli,careful consideration of the assay conditions and apprecia-tion of methodological variability are required, along withqualitative inspection of the aggregation curve, in order todefine the response to stimuli, as in the case of ADP [9]. Adirect comparison of different studies is not feasible whenthreshold doses of agonists rather than the amplitude ofthe aggregation curve is used to quantify the plateletresponse to an agonist, defining an inhibitory effect thatcould be missed if high doses of the agonist are used.Difficulties are also generated by the absence of a prede-fined value of platelet aggregation that defines a mean-ingful biological effect. This is, for instance, the case foraspirin and nonsteroidal anti-inflammatory drugs, forwhich platelet aggregation is ‘inappropriately sensitive’as an index of platelet function when compared withthe generation of thromboxane A2, the biomarker ofplatelet cyclo-oxygenase activity [10]. Light transmissionaggregometry is an ex vivo analysis of platelet functionthat may not be adequate to detect transient effects thatoccur in vivo, such as those depending on the release ofnitric oxide in the case of nebivolol [7]. Other tests, usefulto quantify platelet activation in vivo, have been devel-oped. Soluble P-selectin, which is shed from activatedplatelets, has been used extensively to assess the patho-physiology of atherothrombosis, but only in a limitednumber of studies investigating the effects of antiplateletagents and β-blockers [11]. Finally, functional tests orbiomarkers of in vivo platelet activation need to be strictlyrelated to the biochemical effect of the studied drug, as isthe measurement of thromboxane A2 with aspirin [10].Platelet functionality may be altered as a consequence ofthe clinical characteristics of the studied subjects, and thismay represent a confounder limiting the identificationof pharmacodynamic effects when nonspecific tests areapplied.
Disregarding technical problems related to LTA, ‘tradi-tional bias’ associated with meta-analyses, especiallyselection bias, should be pursued, even more than in tra-ditional clinically oriented meta-analyses. Measures of het-erogeneity should be reported clearly and sensitivityanalysis deepened.
To improve the reliability of meta-analyses, gradingscales to measure the quality of primary studies areincreasingly used [12]. Unfortunately, most of these scaleshave been created to suit clinical trials in comparison withobservational studies and refer to randomization, blind-ness etc. In the specific case of meta-analyses of studiesusing surrogate end-points, a grading scale should ideallybe created also taking into account the specific devicesand procedures used.
In the absence of large-scale clinical trials addressingthe prevention of cardiovascular events with differentβ-blockers, the meta-analysis performed by Bonten et al.
sheds light on the elusive antiplatelet activity of β-blockersusing strict criteria in study selection and definition of theparameters of platelet function analysis [1]. Although notthe ideal test, LTA is suitable for a preliminary investigationof β-blockers with potential antiplatelet activity wheneither healthy subjects or patients were considered. Toovercome methodological imitations, data concerningplatelet aggregation were normalized and groupedaccording to the clinical conditions of the studied subjects,duration of exposure, platelet agonists and the protocolsused in the analysis of aggregation [1].
This careful inspection of existing data now definesa previously unappreciated antiplatelet activity ofβ-blockers and raises interest in the underlying mecha-nisms and its clinical implications.
Extensive evidence of cardiovascular protectionwith β-blockers has been obtained from large-scalerandomized clinical trials and meta-analyses. However,limited information is available from head-to-head com-parisons of new and old compounds concerning majorcardiovascular events. Heterogeneity among individualcompounds appears evident. The evidence of anantiplatelet activity endowed in some β-blockers needs tobe substantiated by further clinical investigation.
Competing Interests
All authors have completed the Unified Competing Inter-est form at http://www.icmje.org/coi_disclosure.pdf (avail-able on request from the corresponding author) anddeclare: no support from any organization for the submit-ted work for the submitted work; no financial relationshipswith any organizations that might have an interest in thesubmitted work in the previous 3 years; no other relation-ships or activities that could appear to have influenced thesubmitted work.
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RECEIVED26 May 2014
ACCEPTED31 May 2014
ACCEPTED ARTICLE PUBLISHED ONLINE9 June 2014
CORRESPONDENCEProfessor Pietro Minuz MD, Department of Medicine, Section ofInternal Medicine, University of Verona, Policlinico GB Rossi,Piazzale LA Scuro, 10, 37134 Verona, Italy.Tel.: +39 45 812 4414Fax: +39 45 802 7465E-mail: [email protected]
Commentary
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