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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Algorithm with suggestions for the decision-making process in patients with drug-related bradycardia&#46; AF&#58; atrial fibrillation&#59; AV&#58; atrioventricular&#59; ECG&#58; electrocardiographic&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Advanced age is&#44; unsurprisingly&#44; one of the most important predisposing factors for adverse drug reactions &#40;ADRs&#41; and ADR-related hospital admissions&#46; Elderly patients are more often on polypharmacy and have more extensive comorbidity&#44; which increase the risk of ADRs through drug-drug or drug-disease interactions and abnormal pharmacokinetics&#46; The higher prevalence of cognitive impairment and functional deficits in this group of patients also impacts on treatment adherence and tolerability&#46; Among elderly patients in particular&#44; ADRs are associated with increased morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1&#44;2</span></a> The most frequent ADRs are typically caused by cardiovascular drugs&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">3</span></a> and a significant percentage of all ADRs involve the cardiovascular system&#44; the most frequent drug-related cardiovascular abnormality probably being bradycardia&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">4</span></a> This is commonly referred to as a type of proarrhythmia&#46; Proarrhythmia can result from a direct effect of the drug on the electrophysiological properties of the conduction system&#44; an abnormal amplification of its effect through drug-drug interactions&#44; or drug-induced metabolic abnormalities&#46; However&#44; although drug-related bradycardia may be seen as a potentially reversible condition likely to subside after discontinuation of the offending drug&#44; a significant percentage of these patients still receive pacemaker implantation during the index admission&#46; Whether this is indeed the right approach in all-comers or just a more cautious&#44; albeit potentially unnecessary one&#44; remains to be determined&#46; The current decision-making process is based on clinical judgment rather than on published guidelines&#44; as little is known about the prognosis of this group of patients&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In this issue of the <span class="elsevierStyleItalic">Journal</span>&#44; Gon&#231;alves et al&#46; present an interesting assessment of the need for permanent pacemaker implantation in elderly patients admitted to hospital due to bradycardia associated with potentially reversible causes such as antiarrhythmic drugs &#40;including beta-blockers&#41; or severe hyperkalemia&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">5</span></a> Their study revealed that more than half of these patients eventually require pacemaker implantation despite discontinuation of the culprit medication and correction of potassium levels&#46; This was particularly true for patients on antiarrhythmic drugs admitted with atrioventricular &#40;AV&#41; conduction abnormalities&#44; while the risk in the setting of sinoatrial dysfunction and&#47;or isolated hyperkalemia was significantly lower&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although there is little doubt on how to treat persistent severe and&#47;or symptomatic bradycardia &#40;most physicians would agree that pacemaker implantation is the right course of action in most&#44; if not all&#44; of these cases&#41;&#44; it remains unclear whether prophylactic pacemaker implantation during the index admission should be offered to patients whose bradycardia resolved after the offending drug was discontinued&#46; The present study offers valuable insight into this matter&#46; The authors&#8217; findings to some extent corroborate the results of the few studies performed to date on this subject and highlight the need for a greater level of attention from physicians caring for these patients&#46; In their assessment of patients with drug-related bradycardia&#44; Lee et al&#46; concluded that&#44; in approximately one quarter of cases&#44; bradycardia persists after discontinuation of the offending drug&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">6</span></a> Similarly&#44; Knudsen et al&#46; reported that 25&#37; of patients who were discharged without a permanent pacemaker subsequently presented with recurrent AV block requiring this treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">7</span></a> Another study revealed that 56&#37; of patients for whom drug discontinuation led to resolution of AV block had recurrence in the absence of antiarrhythmic therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">8</span></a> These studies&#44; together with that of Gon&#231;alves et al&#46;&#44; justify Zeltser&#39;s comment that AV block is commonly &#8220;related to drugs&#8221; but is rarely &#8220;caused by drugs&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">8</span></a> Indeed&#44; given the advanced age of most patients admitted due to drug-induced bradycardia&#44; it is probable that antiarrhythmic drugs are simply unmasking underlying conduction system disease that would otherwise have gone unnoticed for some time&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The management of patients for whom drug discontinuation led to resolution of the index bradycardia involves two critical steps&#58; a decision on whether to implant a prophylactic pacemaker during or soon after the index hospitalization&#59; and&#44; for those discharged without a pacemaker&#44; a commitment to close follow-up with periodic and perhaps long-term continuous monitoring&#46; For elderly patients whose bradycardia resolves after drug discontinuation&#44; it is not unreasonable to offer permanent pacemaker implantation when at least one of the following criteria is met&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">High risk of recurrent severe and&#47;or symptomatic bradycardia&#44; such as in patients who present with high-degree AV block and have a QRS width &#8805;120 ms<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">9</span></a> &#40;measured after the AV block subsided&#41;&#44; or a history of heart failure and&#47;or permanent atrial fibrillation&#44; each of which nearly triples the odds of developing bradycardia requiring pacemaker implantation&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> Also&#44; chronic amiodarone therapy for atrial fibrillation in women&#44; given the long half-life of this drug and the increased risk of pacemaker implantation in elderly women taking this medication<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">11</span></a>&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">History of trauma caused by the proarrhythmia or high risk of sustaining significant physical injury in the event of recurrent bradycardia&#44; which would include a significant percentage of these patients given their advanced age and comorbidity&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Previous indication for beta-blockers on prognostic grounds&#44; for instance those with heart failure or previous myocardial infarction&#44; as discontinuation of this drug could lead to worse outcome&#46;</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">For patients who do not fulfill any of these criteria&#44; particularly if the baseline arrhythmia involves the sinoatrial node rather than the AV node and the patient was taking a high-dose chronotropic drug &#40;or multiple drugs&#41;&#44; a conservative approach with close follow-up is reasonable&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> provides some general guidance on how to manage these cases&#44; although it should be stressed that common sense must prevail at all times&#46; Formal risk stratification models such as the San Francisco Syncope Rule<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">12</span></a> or Risk Stratification of Syncope in the Emergency Department &#40;ROSE&#41;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">13</span></a> score may help identify patients who can safely be discharged after presenting with syncope&#44; but these scores have a very low specificity&#44; which could result in unnecessary treatment or hospitalization for some patients&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">It should be emphasized that drug-induced bradycardia is not the only type of drug proarrhythmia of which physicians should be aware&#46; Polymorphic ventricular tachycardia &#40;VT&#41; and torsade de pointes &#40;TdP&#41; due to drug-related acquired long QT syndrome can also be triggered by various medications&#44; including non-cardiovascular drugs&#44; and it should be noted that these conditions are not always truly reversible&#46; Similar to the concept&#44; mentioned above&#44; of unmasking underlying conduction system disease&#44; drug-induced inhibition of the cardiac hERG&#47;IKr potassium channel may lead to QT prolongation and TdP in patients with other repolarization stressors&#44; including bradycardia&#46; As some of the major epidemiological risk factors for QT prolongation and TdP&#44; such as older age&#44; female gender&#44; heart failure&#44; history of myocardial infarction and metabolic abnormalities&#44; are also predictors of bradyarrhythmia in patients on antiarrhythmic therapy&#44; physicians should bear in mind that some of these patients who present with severe bradycardia may also be at risk of polymorphic VT or TdP&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The relevance and interest of the present study notwithstanding&#44; some final points should be noted&#46; Firstly&#44; these data cannot be extrapolated to young or middle-aged adults admitted due to iatrogenic bradycardia&#44; as the underlying substrate and etiology may be different in this setting&#46; While a degenerative etiology is by far the most common in older patients&#44; advanced AV conduction abnormalities in younger patients are often congenital or associated with autoimmune or infiltrative disorders&#44; including cardiac sarcoidosis&#44; or with pathological hypervagotonia&#44; in which case the investigation is likely to proceed differently&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">14</span></a> Secondly&#44; as mentioned by the authors&#44; the reader should be aware that more prolonged electrocardiographic monitoring&#44; either in-hospital or ambulatory&#44; could detect asymptomatic episodes of advanced AV block warranting pacemaker implantation&#46; This would in fact strengthen the authors&#8217; conclusions by increasing the number of patients requiring a permanent pacemaker&#46; Thirdly&#44; given the retrospective and single-center nature of this study&#44; the possibility of selection bias should not be underestimated&#46; Finally&#44; their assessment of predictors of the need for pacemaker implantation is limited by the small size of the study sample and low number of available variables&#44; and therefore these specific findings should be interpreted with caution&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In summary&#44; elderly patients admitted to hospital due to presumably reversible bradycardia&#44; in particular those with AV block&#44; are at high risk of requiring a permanent pacemaker even after discontinuation of the culprit medication&#46; Consideration should be given to prophylactic pacemaker implantation in patients deemed to be at higher risk of recurrence or physical injury&#44; and others should be monitored in an observational unit and&#44; if discharged&#44; kept under close surveillance with periodic or continuous ambulatory monitoring&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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Editorial comment
Iatrogenic bradyarrhythmia: A benign phenomenon?
Bradiarritmia iatrogénica: um fenómeno benigno?
Sérgio Barraa,b,c,d
a Cardiology Department, Hospital da Luz Arrabida, V. N. Gaia, Portugal
b Cardiology Department, Hospital da Luz Guimarães, Guimarães, Portugal
c Cardiology Department, Centro Hospitalar de Vila Nova de Gaia, V. N. Gaia, Portugal
d Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Advanced age is&#44; unsurprisingly&#44; one of the most important predisposing factors for adverse drug reactions &#40;ADRs&#41; and ADR-related hospital admissions&#46; Elderly patients are more often on polypharmacy and have more extensive comorbidity&#44; which increase the risk of ADRs through drug-drug or drug-disease interactions and abnormal pharmacokinetics&#46; The higher prevalence of cognitive impairment and functional deficits in this group of patients also impacts on treatment adherence and tolerability&#46; Among elderly patients in particular&#44; ADRs are associated with increased morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">1&#44;2</span></a> The most frequent ADRs are typically caused by cardiovascular drugs&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">3</span></a> and a significant percentage of all ADRs involve the cardiovascular system&#44; the most frequent drug-related cardiovascular abnormality probably being bradycardia&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">4</span></a> This is commonly referred to as a type of proarrhythmia&#46; Proarrhythmia can result from a direct effect of the drug on the electrophysiological properties of the conduction system&#44; an abnormal amplification of its effect through drug-drug interactions&#44; or drug-induced metabolic abnormalities&#46; However&#44; although drug-related bradycardia may be seen as a potentially reversible condition likely to subside after discontinuation of the offending drug&#44; a significant percentage of these patients still receive pacemaker implantation during the index admission&#46; Whether this is indeed the right approach in all-comers or just a more cautious&#44; albeit potentially unnecessary one&#44; remains to be determined&#46; The current decision-making process is based on clinical judgment rather than on published guidelines&#44; as little is known about the prognosis of this group of patients&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In this issue of the <span class="elsevierStyleItalic">Journal</span>&#44; Gon&#231;alves et al&#46; present an interesting assessment of the need for permanent pacemaker implantation in elderly patients admitted to hospital due to bradycardia associated with potentially reversible causes such as antiarrhythmic drugs &#40;including beta-blockers&#41; or severe hyperkalemia&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">5</span></a> Their study revealed that more than half of these patients eventually require pacemaker implantation despite discontinuation of the culprit medication and correction of potassium levels&#46; This was particularly true for patients on antiarrhythmic drugs admitted with atrioventricular &#40;AV&#41; conduction abnormalities&#44; while the risk in the setting of sinoatrial dysfunction and&#47;or isolated hyperkalemia was significantly lower&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although there is little doubt on how to treat persistent severe and&#47;or symptomatic bradycardia &#40;most physicians would agree that pacemaker implantation is the right course of action in most&#44; if not all&#44; of these cases&#41;&#44; it remains unclear whether prophylactic pacemaker implantation during the index admission should be offered to patients whose bradycardia resolved after the offending drug was discontinued&#46; The present study offers valuable insight into this matter&#46; The authors&#8217; findings to some extent corroborate the results of the few studies performed to date on this subject and highlight the need for a greater level of attention from physicians caring for these patients&#46; In their assessment of patients with drug-related bradycardia&#44; Lee et al&#46; concluded that&#44; in approximately one quarter of cases&#44; bradycardia persists after discontinuation of the offending drug&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">6</span></a> Similarly&#44; Knudsen et al&#46; reported that 25&#37; of patients who were discharged without a permanent pacemaker subsequently presented with recurrent AV block requiring this treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">7</span></a> Another study revealed that 56&#37; of patients for whom drug discontinuation led to resolution of AV block had recurrence in the absence of antiarrhythmic therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">8</span></a> These studies&#44; together with that of Gon&#231;alves et al&#46;&#44; justify Zeltser&#39;s comment that AV block is commonly &#8220;related to drugs&#8221; but is rarely &#8220;caused by drugs&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">8</span></a> Indeed&#44; given the advanced age of most patients admitted due to drug-induced bradycardia&#44; it is probable that antiarrhythmic drugs are simply unmasking underlying conduction system disease that would otherwise have gone unnoticed for some time&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The management of patients for whom drug discontinuation led to resolution of the index bradycardia involves two critical steps&#58; a decision on whether to implant a prophylactic pacemaker during or soon after the index hospitalization&#59; and&#44; for those discharged without a pacemaker&#44; a commitment to close follow-up with periodic and perhaps long-term continuous monitoring&#46; For elderly patients whose bradycardia resolves after drug discontinuation&#44; it is not unreasonable to offer permanent pacemaker implantation when at least one of the following criteria is met&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">High risk of recurrent severe and&#47;or symptomatic bradycardia&#44; such as in patients who present with high-degree AV block and have a QRS width &#8805;120 ms<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">9</span></a> &#40;measured after the AV block subsided&#41;&#44; or a history of heart failure and&#47;or permanent atrial fibrillation&#44; each of which nearly triples the odds of developing bradycardia requiring pacemaker implantation&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">10</span></a> Also&#44; chronic amiodarone therapy for atrial fibrillation in women&#44; given the long half-life of this drug and the increased risk of pacemaker implantation in elderly women taking this medication<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">11</span></a>&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">History of trauma caused by the proarrhythmia or high risk of sustaining significant physical injury in the event of recurrent bradycardia&#44; which would include a significant percentage of these patients given their advanced age and comorbidity&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Previous indication for beta-blockers on prognostic grounds&#44; for instance those with heart failure or previous myocardial infarction&#44; as discontinuation of this drug could lead to worse outcome&#46;</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">For patients who do not fulfill any of these criteria&#44; particularly if the baseline arrhythmia involves the sinoatrial node rather than the AV node and the patient was taking a high-dose chronotropic drug &#40;or multiple drugs&#41;&#44; a conservative approach with close follow-up is reasonable&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> provides some general guidance on how to manage these cases&#44; although it should be stressed that common sense must prevail at all times&#46; Formal risk stratification models such as the San Francisco Syncope Rule<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">12</span></a> or Risk Stratification of Syncope in the Emergency Department &#40;ROSE&#41;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">13</span></a> score may help identify patients who can safely be discharged after presenting with syncope&#44; but these scores have a very low specificity&#44; which could result in unnecessary treatment or hospitalization for some patients&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">It should be emphasized that drug-induced bradycardia is not the only type of drug proarrhythmia of which physicians should be aware&#46; Polymorphic ventricular tachycardia &#40;VT&#41; and torsade de pointes &#40;TdP&#41; due to drug-related acquired long QT syndrome can also be triggered by various medications&#44; including non-cardiovascular drugs&#44; and it should be noted that these conditions are not always truly reversible&#46; Similar to the concept&#44; mentioned above&#44; of unmasking underlying conduction system disease&#44; drug-induced inhibition of the cardiac hERG&#47;IKr potassium channel may lead to QT prolongation and TdP in patients with other repolarization stressors&#44; including bradycardia&#46; As some of the major epidemiological risk factors for QT prolongation and TdP&#44; such as older age&#44; female gender&#44; heart failure&#44; history of myocardial infarction and metabolic abnormalities&#44; are also predictors of bradyarrhythmia in patients on antiarrhythmic therapy&#44; physicians should bear in mind that some of these patients who present with severe bradycardia may also be at risk of polymorphic VT or TdP&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The relevance and interest of the present study notwithstanding&#44; some final points should be noted&#46; Firstly&#44; these data cannot be extrapolated to young or middle-aged adults admitted due to iatrogenic bradycardia&#44; as the underlying substrate and etiology may be different in this setting&#46; While a degenerative etiology is by far the most common in older patients&#44; advanced AV conduction abnormalities in younger patients are often congenital or associated with autoimmune or infiltrative disorders&#44; including cardiac sarcoidosis&#44; or with pathological hypervagotonia&#44; in which case the investigation is likely to proceed differently&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">14</span></a> Secondly&#44; as mentioned by the authors&#44; the reader should be aware that more prolonged electrocardiographic monitoring&#44; either in-hospital or ambulatory&#44; could detect asymptomatic episodes of advanced AV block warranting pacemaker implantation&#46; This would in fact strengthen the authors&#8217; conclusions by increasing the number of patients requiring a permanent pacemaker&#46; Thirdly&#44; given the retrospective and single-center nature of this study&#44; the possibility of selection bias should not be underestimated&#46; Finally&#44; their assessment of predictors of the need for pacemaker implantation is limited by the small size of the study sample and low number of available variables&#44; and therefore these specific findings should be interpreted with caution&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In summary&#44; elderly patients admitted to hospital due to presumably reversible bradycardia&#44; in particular those with AV block&#44; are at high risk of requiring a permanent pacemaker even after discontinuation of the culprit medication&#46; Consideration should be given to prophylactic pacemaker implantation in patients deemed to be at higher risk of recurrence or physical injury&#44; and others should be monitored in an observational unit and&#44; if discharged&#44; kept under close surveillance with periodic or continuous ambulatory monitoring&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleLabel">1</span><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0060" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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